Modulators of cystic fibrosis transmembrane conductance regulator

ABSTRACT

The present invention features a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , W, X, Y, Z, n, o, p, and q are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present invention also features pharmaceutical compositions, method of treating, and kits thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. § 119 toU.S. provisional patent application Ser. Nos. 62/060,182, filed Oct. 6,2014; 62/114,767, filed Feb. 11, 2015; and 62/153,120, filed Apr. 27,2015, the entire contents of all applications are incorporated herein byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention features modulators of Cystic FibrosisTransmembrane Conductance Regulator (CFTR), pharmaceutical compositions,methods of treatment, and kits thereof.

BACKGROUND OF THE INVENTION

Cystic fibrosis (CF) is a recessive genetic disease that affectsapproximately 30,000 children and adults in the United States andapproximately 30,000 children and adults in Europe. Despite progress inthe treatment of CF, there is no cure.

In patients with CF, mutations in CFTR endogenously expressed inrespiratory epithelia leads to reduced apical anion secretion causing animbalance in ion and fluid transport. The resulting decrease in aniontransport contributes to enhanced mucus accumulation in the lung and theaccompanying microbial infections that ultimately cause death in CFpatients. In addition to respiratory disease, CF patients typicallysuffer from gastrointestinal problems and pancreatic insufficiency that,if left untreated, results in death. In addition, the majority of maleswith cystic fibrosis are infertile and fertility is decreased amongfemales with cystic fibrosis. In contrast to the severe effects of twocopies of the CF associated gene, individuals with a single copy of theCF associated gene exhibit increased resistance to cholera and todehydration resulting from diarrhea—perhaps explaining the relativelyhigh frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed avariety of disease causing mutations (Cutting, G. R. et al. (1990)Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem,B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc.Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 1000 diseasecausing mutations in the CF gene have been identified(http://cftr2.org). The most prevalent mutation is a deletion ofphenylalanine at position 508 of the CFTR amino acid sequence, and iscommonly referred to as F508del. This mutation occurs in approximately70% of the cases of cystic fibrosis and is associated with a severedisease.

The deletion of residue 508 in F508del prevents the nascent protein fromfolding correctly. This results in the inability of the mutant proteinto exit the ER, and traffic to the plasma membrane. As a result, thenumber of channels present in the membrane is far less than observed incells expressing wild-type CFTR. In addition to impaired trafficking,the mutation results in defective channel gating. Together, the reducednumber of channels in the membrane and the defective gating lead toreduced anion transport across epithelia leading to defective ion andfluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studieshave shown, however, that the reduced numbers of F508del in the membraneare functional, albeit less than wild-type CFTR. (Dalemans et al.(1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk andFoskett (1995), J. Cell. Biochem. 270: 12347-50). In addition toF508del, other disease causing mutations in CFTR that result indefective trafficking, synthesis, and/or channel gating could be up- ordown-regulated to alter anion secretion and modify disease progressionand/or severity.

Accordingly, there is a need for novel treatments of CFTR mediateddiseases.

SUMMARY OF THE INVENTION

The invention features a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring A is a C6-C10 aryl ring; C3-C10 cycloalkyl ring; or a        C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   Ring B is a C3-C10 cycloalkyl ring; a C6-C10 aryl ring; or a        C4-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring; a C3-C14 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently N, NR, O, or S; or a C3-C10 cycloalkyl ring;    -   W is O, NR, or S;    -   X is O or NR;    -   Y is independently CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   Z is NR or CHR;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are optionally and independently replaced with        O, CO, S, SO, SO₂ or NR;    -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; OH; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6        alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH;CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5;    -   is a single bond or a double bond;        provided that the moieties containing ring B and ring C are        substituted at adjacent positions on ring A.

The present invention also features pharmaceutical compositions thereof,which may include additional agents, and methods of treating CFTRmediated diseases, such as cystic fibrosis, comprising administeringcompounds of formula I to a subject in need thereof. The presentinvention also features kits comprising compounds of formula I.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 discloses a list of CFTR mutations by name, protein name, andlegacy name that in one aspect of the invention a patient may possessand be treatable by the compounds and compositions of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, “CFTR” stands for cystic fibrosis transmembraneconductance regulator.

As used herein, “mutations” can refer to mutations in the CFTR gene orthe CFTR protein. A “CFTR mutation” refers to a mutation in the CFTRgene, and a “CFTR mutation” refers to a mutation in the CFTR protein. Agenetic defect or mutation, or a change in the nucleotides in a gene ingeneral results in a mutation in the CFTR protein translated from thatgene.

As used herein, a “F508del mutaion” or “F508del” is a specific mutationwithin the CFTR protein. The mutation is a deletion of the threenucleotides that comprise the codon for amino acid phenylalanine atposition 508, resulting in CFTR protein that lacks this phenylalanineresidue.

The term “CFTR gating mutation” as used herein means a CFTR mutationthat results in the production of a CFTR protein for which thepredominant defect is a low channel open probability compared to normalCFTR (Van Goor, F., Hadida S. and Grootenhuis P., “PharmacologicalRescue of Mutant CFTR function for the Treatment of Cystic Fibrosis”,Top. Med. Chem. 3: 91-120 (2008)). Gating mutations include, but are notlimited to, G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N,S1255P, and G1349D.

As used herein, a patient who is “homozygous” for a particular mutation,e.g. F508del, has the same mutation on each allele.

As used herein, a patient who is “heterozygous” for a particularmutation, e.g. F508del, has this mutation on one allele, and a differentmutation on the other allele.

As used herein, the term “modulator” refers to a compound that increasesthe activity of a biological compound such as a protein. For example, aCFTR modulator is a compound that increases the activity of CFTR. Theincrease in activity resulting from a CFTR modulator may be through acorrector mechanism or a potentiator mechanism as described below.

As used herein, the term “CFTR corrector” refers to a compound thatincreases the amount of functional CFTR protein to the cell surface,resulting in enhanced ion transport.

As used herein, the term “CFTR potentiator” refers to a compound thatincreases the channel activity of CFTR protein located at the cellsurface, resulting in enhanced ion transport.

As used herein, the term “inducing,” as in inducing CFTR activity,refers to increasing CFTR activity, whether by the corrector,potentiator, or other mechanism.

As used herein, the term “active pharmaceutical ingredient” or “API”refers to a biologically active compound.

A “patient,” “subject” or “individual” are used interchangeably andrefer to either a human or non-human animal. The term includes mammalssuch as humans.

The terms “effective dose” or “effective amount” are usedinterchangeably herein and refer to that amount that produces thedesired effect for which it is administered (e.g., improvement in CF ora symptom of CF or lessening the severity of CF or a symptom of CF). Theexact amount will depend on the purpose of the treatment, and will beascertainable by one skilled in the art using known techniques (see,e.g., Lloyd (1999) The Art, Science and Technology of PharmaceuticalCompounding).

As used herein, the terms “treatment,” “treating,” and the likegenerally mean the improvement of CF or its symptoms or lessening theseverity of CF or its symptoms in a subject. “Treatment,” as usedherein, includes, but is not limited to, the following: increased growthof the subject, increased weight gain, reduction of mucus in the lungs,improved pancreatic and/or liver function, reduced cases of chestinfections, and/or reduced instances of coughing or shortness of breath.Improvements in or lessening the severity of any of these conditions canbe readily assessed according to standard methods and techniques knownin the art.

As used herein, the term “in combination with” when referring to two ormore compounds or agents means that the order of administration includesthe compounds or agents being administered prior to, concurrent with, orsubsequent to each other to the patient.

As used herein, the phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted.”

As described herein, compounds within the compositions of the inventioncan optionally be substituted with one or more substituents, such as areillustrated generally above, or as exemplified by particular classes,subclasses, and species of the invention (such as the compounds listedin Table 1). As described herein in formulae I-Id-ii , the variablesR₁-R₄ in formulae I-Id-ii encompass specific groups, such as, forexample, alkyl, alkenyl, alkynyl, alkoxy, heteroaryl, heterocyclic,cycloalkyl, and aryl, etc. Unless otherwise noted, each of the specificgroups for the variables R₁-R₄ can be optionally substituted with one ormore group selected from halo, phospho, OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, fluoroalkyl, alkyl, alkenyl,alkynyl, nitro, CN, hydroxyl, and (C1-C9alkylene)-E wherein up to 4 CH₂units are independently replaced with O, S, SO₂, SO, CO, NH, N-alkyl,N-alkenyl, or N-alkynyl, and E is H, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, alkoxy, CN, or CF₃, further wherein each of the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substitutedwith one or more group selected from halo, alkyl, amino, CN, alkenyl,alkynyl, and alkoxy.

As one of ordinary skill in the art will recognize, combinations ofsubstituents envisioned by this invention are those combinations thatresult in the formation of stable or chemically feasible compounds. Theterm “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and preferably their recovery, purification, anduse for one or more of the purposes disclosed herein. In someembodiments, a stable compound or chemically feasible compound is onethat is not substantially altered when kept at a temperature of 40° C.or less, in the absence of moisture or other chemically reactiveconditions, for at least a week. When two alkoxy groups are bound to thesame atom or adjacent atoms, the two alkoxy groups can form a ringtogether with the atom(s) to which they are bound.

As disclosed herein, substituents or variables (such as R and R₁-R₄ informula I-Id-ii) can be selected from more than one specific group. Tothe extent that one specific group for a variable may include or overlapwith another specific group for the same variable, the narrower specificgroup is provisoed out from the broader specific group. In other words,double inclusion cannot exist.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. As one of ordinary skillin the art will recognize, combinations of substituents envisioned bythis invention are those combinations that result in the formation ofstable or chemically feasible compounds.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3.

The terms “about” and “approximately”, when used in connection withdoses, amounts, or weight percent of ingredients of a composition or adosage form, mean a dose, amount, or weight percent that is recognizedby one of ordinary skill in the art to provide a pharmacological effectequivalent to that obtained from the specified dose, amount, or weightpercent. Specifically the term “about” or “approximately” means anacceptable error for a particular value as determined by one of ordinaryskill in the art, which depends in part on how the value is measured ordetermined. In certain embodiments, the term “about” or “approximately”means within 1, 2, 3, or 4 standard deviations. In certain embodiments,the term “about” or “approximately” means within 30%, 25%, 20%, 15%,10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a givenvalue or range.

The term “adjacent” as used herein refers to positions on the ringwherein the two ring atoms are bonded to each other. Two ring atoms withan intervening ring atom are not considered adjacent even when thatintervening atom does not allow substitution due to valency.

The term “aliphatic”, “aliphatic group,” as used herein, means astraight-chain (i.e., unbranched) or branched hydrocarbon chain that iscompletely saturated or that contains one or more units of unsaturation.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphaticgroups include, but are not limited to, linear or branched, substitutedor unsubstituted alkyl, alkenyl, alkynyl groups.

The term “spiro” as used herein, means a two-ring system wherein bothrings share only one common atom.

The term “cycloaliphatic” or “cycloalkyl” mean a monocyclic, bicyclic(fused or spiro), tricyclic (fused or spiro), or propellane hydrocarbonthat has a single point of attachment to the rest of the molecule, andthat is completely saturated or contains one or more units ofunsaturation, but none of the individual rings in the monocyclic,bicyclic, or tricyclic hydrocarbon is aromatic. The single point ofattachment can be on the saturated or unsaturated carbon. In someembodiments, “cycloaliphatic” or “cycloalkyl” refers to a monocyclicC₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but noneof the individual ring in the monocyclic C₃-C₈ hydrocarbon or fusedbicyclic C₈-C₁₂ hydrocarbon is aromatic, and that has a single point ofattachment to the rest of the molecule wherein any individual ring insaid bicyclic ring system has 3-7 members.

As used herein, an “alkyl” group refers to a saturated hydrocarbon groupcontaining 1-20 (e.g., 1-6 or 1-12) carbon atoms. An alkyl group can bestraight or branched. Examples of alkyl groups include, but are notlimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl.

As used herein, an “alkenyl” group refers to a hydrocarbon group thatcontains 2-20 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at least onedouble bond. Like an alkyl group, an alkenyl group can be straight orbranched. The point of attachement can be on a saturated carbon orunsaturated carbon. Examples of an alkenyl group include, but are notlimited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl.

As used herein, an “alkynyl” group refers to a hydrocarbon group thatcontains 2-20 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has at leastone triple bond. An alkynyl group can be straight or branched. The pointof attachement can be on a saturated carbon or unsaturated carbon.Examples of an alkynyl group include, but are not limited to, propargyland butynyl.

As used herein, an “alkoxy” group refers to —O-alkyl, O-alkenyl, orO-alknyl, wherein alkyl, alkenyl, and alkynyl are as defined above.

As used herein, “fluoroalkyl” or “fluoroalkoxy” refers to alkyl oralkoxy wherein one or more hydrogen is substituted with a fluoro.

As used herein, an “amino” refers to NH₂ which is optionally substitutedwith one or two groups independently selected from alkyl, cycloalkyl,and heterocycloalkyl.

The term “electron withdrawing group”, as used herein means an atom or agroup that is electronegative relative to hydrogen. See, e.g., “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure,” Jerry March,4^(th) Ed., John Wiley & Sons (1992), e.g., pp. 14-16, 18-19, etc.Exemplary such substituents include halo such as Cl, Br, or F, CN, COOH,CF₃, etc.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, “heterocycloalkyl” or “heterocyclic” as usedherein means monocyclic, bicyclic (fused or spiro), tricyclic (fused orspiro), or propellane ring systems in which one or more ring atoms inone or more ring members is an independently selected heteroatom andnone of the individual rings in the system is aromatic. Heterocyclicrings can be saturated or can contain one or more unsaturated bonds. Insome embodiments, the “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, “heterocycloalkyl”or “heterocyclic” group hasthree to fourteen ring members in which one or more ring members is aheteroatom independently selected from oxygen, sulfur, nitrogen, orphosphorus, and each ring in the ring system contains 3 to 7 ringmembers. The point of attachment can be on the carbon or heteroatom.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic(fused), and tricyclic (fused or spiro) hydrocarbon ring systems havinga total of five to fourteen ring carbon atoms, wherein at least one ringin the system is aromatic and wherein each ring in the system contains 3to 7 ring carbon atoms. The term “aryl” may be used interchangeably withthe term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic(fused), and tricyclic (fused or spiro) ring systems having a total offive to fourteen ring members, wherein at least one ring in the systemis aromatic, at least one ring in the system contains one or moreheteroatoms, and wherein each ring in the system contains 3 to 7 ringmembers. The term “heteroaryl” may be used interchangeably with the term“heteroaryl ring” or the term “heteroaromatic”.

The term “alkylene” refers to a straight or branched hydrocarbon chainthat may be fully saturated or have one or more units of unsaturationand has two points of attachment to the rest of the molecule.

The term “prodrug,” as used herein, represents a compound that istransformed in vivo into a compound according to any one of the formulaelisted herein. Such a transformation can be affected, for example, byhydrolysis in blood or enzymatic transformation of the prodrug form tothe parent form in blood or tissue. Prodrugs of the compounds of theinvention may be, for example, amides. Amides that may be utilized asprodrugs in the present invention are phenyl amides, aliphatic (C₁-C₂₄)amids, acyloxymethyl amides, ureas, carbamates, and amino acid amides.For example, a compound of the invention that contains an NH group maybe acylated at this position in its prodrug form. Other prodrug formsinclude esters, such as, for example phenyl esters, aliphatic (C₁-C₂₄)esters, acyloxymethyl esters, carbonates, carbamates, and amino acidesters. A thorough discussion of prodrugs is provided in T. Higuchi andV. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987,and Judkins et al., Synthetic Communications 26(23):4351-4367, 1996,each of which is incorporated in its entirety herein by reference. Insome embodiments, the present invention features a prodrug of any one ofthe formulas or compounds listed herein.

The term “isosteres” or “bioisosteres,” as used herein, refers tocompounds resulting from the exchange of an atom or group of atoms tocreate a new compound with similar biological properties to the parentcompound. The bioisosteric replacement may be physicochemically ortopologically based. For example, an isosteric replacement for a carboxcacid is CONHSO₂(alkyl or aryl)) such as CONHSO₂Me. A further discussionof isosterism is provided in R. Silverman, The Organic Chemistry of DrugDesign and Drug Action, second edition, Elsevier Academic Press, 2004,incorporated in its entirety herein by reference. In some embodiments,the present invention features a isostere of any one of the formulas orcompounds listed herein.

In the formulas and drawings, a line transversing a ring and bonded toan R group such as, for example, R₂ in the following formula

means that the R group can be bonded to any carbon, or if applicable,heteroatom such as N, of that ring, including any fused ring, as valencyallows.

Within a term definition as, for example, R₁ through R₃ when a CH₂ unitor, interchangeably, a methylene unit may be replaced by O, CO, S, SO,SO₂, or NR; it is meant to include any CH7 unit, including a CH₂ withina terminal methyl or methylene group. For example, —CH₂CH2CH₂SH iswithin the definition of C1-C9 alkylene-R₄ wherein up to four CH₂ unitsare independently replaced by O, CO, S, SO, SO₂, or NR because the CH₂unit of the terminal methyl group has been replaced by S. The analogousapplies to such definitions as —CH₂CH₂OH, —CH₂CH₂CN, or —CH₂CH₂NH₂.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Where the enantiomers of a racemicmixture have been separated, but the absolute chemistry has not yet beendetermined, the compound's structure is depicted with a wavy line.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention. Thus, included withinthe scope of the invention are tautomers of compounds of formulas I toId-ii.

To the extent that a definition in the present application differs fromany definition in an application incorporated by reference, thedefinition in the present application supercedes.

CFTR is a cAMP/ATP-mediated anion channel that is expressed in a varietyof cells types, including absorptive and secretory epithelia cells,where it regulates anion flux across the membrane, as well as theactivity of other ion channels and proteins. In epithelia cells, normalfunctioning of CFTR is critical for the maintenance of electrolytetransport throughout the body, including respiratory and digestivetissue. CFTR is composed of approximately 1480 amino acids that encode aprotein made up of a tandem repeat of transmembrane domains, eachcontaining six transmembrane helices and a nucleotide binding domain.The two transmembrane domains are linked by a large, polar, regulatory(R)-domain with multiple phosphorylation sites that regulate channelactivity and cellular trafficking.

In patients with cystic fibrosis, mutations in endogenously expressedCFTR lead to reduced apical anion secretion causing an imbalance in ionand fluid transport. The resulting decrease in anion transportcontributes to enhanced mucus accumulation in the lung and theaccompanying microbial infections that ultimately cause death in CFpatients. In addition to respiratory disease, CF patients typicallysuffer from gastrointestinal problems and pancreatic insufficiency that,if left untreated, results in death. In addition, the majority of maleswith cystic fibrosis are infertile and fertility is decreased amongfemales with cystic fibrosis. In contrast to the severe effects of twocopies of the CF associated gene, individuals with a single copy of theCF associated gene exhibit increased resistance to cholera and todehydration resulting from diarrhea-perhaps explaining the relativelyhigh frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed avariety of disease-causing mutations (Cutting, G. R. et al. (1990)Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem,B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc.Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 1000disease-causing mutations in the CF gene have been identified asreported by the scientific and medical literature. The most prevalentmutation is a deletion of phenylalanine at position 508 of the CFTRamino acid sequence, and is commonly referred to as F508del. Thismutation occurs in approximately 70 percent of the cases of cysticfibrosis and is associated with a severe disease. A more complete listof identified mutations can be found at www.cftr2.org.

These elements work together to achieve directional transport across theepithelium via their selective expression and localization within thecell. Chloride absorption takes place by the coordinated activity ofENaC and CFTR present on the apical membrane and the Na⁺—K⁺— ATPase pumpand Cl— channels expressed on the basolateral surface of the cell.Secondary active transport of chloride from the luminal side leads tothe accumulation of intracellular chloride, which can then passivelyleave the cell via Cl⁻ channels, resulting in a vectorial transport.Arrangement of Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump and thebasolateral membrane K⁺ channels on the basolateral surface and CFTR onthe luminal side coordinate the secretion of chloride via CFTR on theluminal side. Because water is probably never actively transporteditself, its flow across epithelia depends on tiny transepithelialosmotic gradients generated by the bulk flow of sodium and chloride.

Compounds of Formula I

In some embodiments the present invention features a compound of formulaI:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring A is a C6-C10 aryl ring; C3-C10 cycloalkyl ring; or a        C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   Ring B is a C3-C10 cycloalkyl ring; a C6-C10 aryl ring; or a        C4-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring ; a C3-C14 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently N, NR, O, or S; or a C3-C10 cycloalkyl ring;    -   W is O, NR, or S;    -   X is O or NR;    -   Y is independently CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   Z is NR or CHR;    -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with 0, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently 0, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;    -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; OH; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6        alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl        ; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5;    -   is a single bond or a double bond;        provided that the moieties containing ring B and ring C are        substituted at adjacent positions on ring A.

In another embodiment, the compounds of the invention are of formula Iand the attendant definitions, provided that: i) when ring A is indole,n is not zero and rings B and C are aryl unsubstituted by CF₃ or halo;ii) when ring A is pyrazole, n is not zero; iii) when ring A is pyridyl,ring B and ring C moieties are substituted at the 2- and 3-positions ofthe pyridyl ring, interchangeably; and iv) when ring A is imidazole, thering B moiety is substituted at the 2-position of the imidazole ring.

In some embodiments, the compounds of the present inventions are in theform of a pharmaceutically acceptable prodrug.

In some embodiments, ring A is a C6-C10 aryl ring, such as a phenyl,indane, 1,2,3,4-tetrahydronaphthalene, or naphthalene. In someemboidments, ring A is a C3-C11 heteroaryl or heterocyclic ring whereinanywhere from 1 to 4 ring atoms are independently O, S, N, or NR, suchas pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine,1,2,3,4-tetrahydroquinoline, quinoline, 5,6,7,8-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole,oxazole, pyrazine, triazole, indazole,2,3,4,5-tetrahydro-1H-benzo[d]azepine, 1H-benzo[d]imidazole, orimidazole ring.

In some embodiments, ring A is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring A is

In some embodiments, ring B is a cycloalkyl ring, such as acyclopropane, cyclobutane, cyclopentane, or cyclohexane. In someembodiments, ring B is a C6-C10 aryl ring, such as a phenyl. In someembodiments, ring B is a heroaryl or heterocyclic ring wherein anywherefrom 1 to 4 ring atoms are independently O, S, N, or NR, such aspyridyl, pyridine-2(1H)-one, pyrazole, indole, indoline, thiophene,dihydrobenzofuran, tetrahydrofuran , furan, pyrazine, indazole,thiazole, pyridine-4(1H)-one, pyrrolidinone, 3-azabicyclo[3.1.0]hexane,(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, pyrrolidine, azetidine,piperidine, piperazine, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is a C6-C10 aryl ring, such as a phenyl,indane, or naphthalene. In some embodiments, ring C is a C3-C10cycloalkyl ring, such as a cyclopropane, cyclobutane, cyclopentane,cyclopentene, cyclohexane, cyclohexene, cycloheptane, or(1s,4s)-bicyclo[2.2.1]heptane. In some embodiments, ring C is a C3-C10heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atomsare indpependently N, NR, O, or S, such as indole, isoindoline,indoline, pyridyl, pyrrolidine, 2,5-dihydro-1H-pyrrole, morpholine,tetrahydro-2H-pyran, tetrahydrofuran, oxetane, piperidine, piperazine,azepane, azetidine, octahydrocyclopenta[c]pyrrole,octahydrocyclopenta[b]pyrrole, octahydro-1H-indole,octahydro-1H-cyclopenta[b]pyridine, (1s,4s)-7-azabicyclo[2.2.1]heptane,2-azabicyclo[4.1.0]heptane, (1S,4R)-2-azabicyclo[2.2.1]heptane,(1R,5S)-8-azabicyclo[3.2.1]octane, 3,6-dihydro-2H-pyran, or(1R,5S)-3-azabicyclo[3.2.1]octane.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, Ring C is

In some embodiments, X is O. In some embodiments, X is NR. In someembodiments, X is NH.

In In some embodiments, Y is O. In some embodiments, Y is CRR, such asCH₂, CH(C1-C6 alkyl), CH(CH₃), or CH(CH₂CH₃). In some embodiments, Y isNR, such as NH, N(C1-C6 alkynyl), or N(C1-C6 alkyl). In someembodiments, (Y)_(o) is a bond, O, NH, (CH₂)_(m), O—(CH₂)_(m), wherem=1-4, CH(CH₃), O—CH(CH₃), O—CH(CH₂CH₃), O—CH(CH₃)CH₂, O—C(CH₃)₂CH₂,O—CH₂CH₂CH(CH₃), N(CH₃), NH—CH₂, N(CH₃)—CH₂, NCH(CH₃)₂—CH₂,N(CH₂CH₂CH₃)—CH₂, NH—CH(CH₃), N(CH₃)—CH(CH₃), or N(CH₂CCH)—CH₂CH₂.

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,azetidine, pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ whereinup to four CH₂ units are independently replaced with O, CO, S, SO, SO₂or NR, wherein all rings are optionally substituted with one or moregroups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl,C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 carbon atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are optionallyand independently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table I. For example R₂ is Cl, F, OH,CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃, CH₃,CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, ring A is

and n is 1. In some embodiments, ring A is

n is 1, and R₁ is tBu. In some embodiments, ring A is

n is 1, and R₁ is phenyl. In some embodiments, ring A is

n is 1, R₁ is phenyl, and Y is O. In some embodiments, ring A is

n is 1, R₁ is tBu, and Y is O. In some emdodiments, ring A is

ring B is pyridyl, and ring C is phenyl. In some embodiments, R₁ isphenyl, R₂ is amino, and R₃ is CH₃.

In some embodiments, ring A is

n is 1, and R₁ is pyridyl. In some embodiments, ring A is

n is 1, R₁ is pyridyl, and o is 0. In some embodiment, ring A is

ring B is pyridyl, and ring C is pyrrolidine.

In some embodiments, ring A is

n is 1, and R₁ is pyrazole. In some embodiments, ring A is

n is 1, R₁ is pyrazole, and o is 0.

In some embodiments, ring A is

n is 1, and R₁ is cycloalkyl. In some embodiments, ring A is

n is 1, R₁ is cycloalkyl, and Y is O. In some emdodiments, ring A is

ring B is pyridyl, and ring C is cycloalkyl. In some embodiments, R₁ iscycloalkyl, R₂ is alkoxy, and R₃ is CH₃.

In some embodiments, ring A is

and n is 1. In some embodiments, ring A is

n is 1, and R₁ is phenyl. In some embodiments, ring A is

n is 1, and R₁ is tBu. In some embodiments, ring A is

n is 1, R₁ is phenyl, and Y is O. In some embodiments, ring A is

n is 1, R₁ is tBu, and Y is O. In one emdodiment, ring A is

ring B is pyridyl, and ring C is phenyl.

In some embodiments, ring A is

and n is 1. In some embodiments, ring A is

n is 1, and R₁ is phenyl. In some embodiments, ring A is

n is 1, and R₁ is tBu. In some embodiments, ring A is

n is 1, R₁ is phenyl, and Y is O. In some embodiments, ring A is

n is 1, R₁ is tBu, and Y is O. In some emdodiment, ring A is

ring B is pyridyl, and ring C is phenyl.

In some embodiments, ring A is

and n is 1. In some embodiments, ring A is

n is 1, and R₁ is phenyl. In some embodiments, ring A is

n is 1, and R₁ is tBu. In some embodiments, ring A is

n is 1, R₁ is phenyl, and Y is O. In some embodiments, ring A is

n is 1, R₁ is tBu, and Y is O. In one emdodiment, ring A is

ring B is pyridyl, and ring C is phenyl.

In some embodiments, the present invention features a compound offormula I-i:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring A is a C3-C14 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently O, S, N, or        NR;    -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring , C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are optionally N,        O, or S, or a C3-C10 cycloalkyl ring;    -   X is O or NR;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   Z is NR or CHR;    -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; Ci-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl        ; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5;        provided that the moieties containing ring B and ring C are        substituted at adjacent positions on ring A.

In some embodiments, the compound of formula I-i exists as apharmaceutically acceptable prodrug.

In some embodiments, ring A is a pyridyl, indole, indoline, isoindoline,pyrazole, pyrimidine, quinoline, 5,6,7,8-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole,oxazole, pyrazine, triazole, indazole, or imidazole ring.

In some embodiments, ring A is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring A is

In some embodiments, ring B is pyridyl, pyridine-2(1H)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, thiazole,pyrrolidinone, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,tetrahydro-2H-pyran, azepane, tetrahydrofuran, pyrrolidine, naphthalene,piperidine, azetidine, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, X is O. In some embodiments, X is NR. In someembodiments, X is NH.

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,azetidine, pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ whereinup to four CH₂ units are independently replaced with O, CO, S, SO, SO₂or NR, wherein all rings are optionally substituted with one or moregroups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl,C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are optionally O, S, N, or NR;and a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are independentlyreplaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, C6-C10 aryl, or C3-C10 heteroaryl or heterocycloalkyl whereinanywhere from 1 to 4 ring atoms are independently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, the compound of formula I is a compound of formulaI-ii:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring A is a C3-C14 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently O, S, N, or        NR;    -   Ring B is a C6-C10 aryl ring;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are optionally N,        O, or S, or a C3-C10 cycloalkyl ring;    -   X is O or NR;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   Z is NR or CHR;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a =CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5;        provided that the moieties containing ring B and ring C are        substituted at adjacent positions on ring A.

In some embodiments, the compound of formula I-ii exists as apharmaceutically acceptable prodrug.

In some embodiments, ring A is a pyridyl, indole, indoline, isoindoline,pyrazole, pyrimidine, quinoline, 5,6,7,8-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole,oxazole, pyrazine, triazole, indazole, or imidazole ring.

In some embodiments, ring A is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring A is

In some embodiments, ring B is phenyl or naphthalene.

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, piperidine, azetidine, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, X is O. In another embodiment, X is NR. In someembodiments, X is NH.

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6 alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,azetidine, pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ whereinup to four CH₂ units are independently replaced with O, CO, S, SO, SO₂or NR, wherein all rings are optionally substituted with one or moregroups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl,C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, C6-C10 aryl, or C3-C10 heteroaryl or heterocycloalkyl whereinanywhere from 1 to 4 ring atoms are independently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. R₃ is Cl, I, deuterium, F,CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH(CH₃)₂,OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH, CH₂CONH₂,CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is O. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is O. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is O. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, the invention features a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring , C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   X is O or NR;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy;C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH;CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, or 2;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ia exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, piperidine, or dihydroindene.

In some embodiments, ring C is is a group represented by thecorresponding moieties shown in the compounds of Table 1. For example,ring C is

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH9CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table I. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, ring B is phenyl. In some embodiments, ring B andring C are phenyl. In some embodiments, R₁ is tBu. In some embodiments,ring B and ring C are phenyl and R₁ is tBu. In some embodiments, Y isCH₂. In some embodiments, ring B and ring C are phenyl, R₁ is tBu, and Yis CH₂. In some embodiments, ring B, ring C, and R₁ are phenyl and Y isCH₂.

In some embodiments, the invention features a compound of formula Ia-i:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   X is O or NR;

1 Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;

-   -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy;C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl        ; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH;CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, or 2;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ia-i exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is pyridyl, pyridine-2(1H)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is,

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, piperidine, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently. O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, =CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, the invention features a compound of formula Ia-ii:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring;    -   Ring C is a C6-C10 aryl ring , C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   X is O or NR;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, or 2;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ia-ii exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl or naphthalene.

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, piperidine, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, the compound of formula I is a compound of formulalb:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 mono- or bicyclic cycloalkyl ring;

Y is CRR, CO, 0, 5, SO, SO₂, S(O)NH or NR;

R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl; C1-C6alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR; C6-C10 aryl; C3-C10 heteroaryl orheterocyclic ring wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR; or C3-C10 cycloalkyl;

-   -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH;CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1,2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula lb exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,naphthalene, pyrrolidine, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂.

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, ring B is pyridyl. In some embodiments, ring B isphenyl. In some embodiments, ring B and ring C are phenyl. In someembodiments, ring B is pyridyl and ring C is phenyl. In someembodiments, Y is CH₂. In some embodiments, Y is O.

In some embodiments, R₁ is aryl. In some embodiments, ring B, ring C,and R₁ are phenyl. In some embodiments, ring B is pyridyl, ring C isphenyl, and R₁ is phenyl. In some embodiments, ring B, ring C, and R₁are phenyl, and Y is CH₂. In some embodiments, ring B, ring C, and R₁are phenyl, and Y is O. In some embodiments, ring B is pyridyl, ring Cis phenyl, R₁ is phenyl, and Y is CH₂. In some embodiments, ring B ispyridyl, ring C is phenyl, R₁ is phenyl, and Y is O.

In some embodiments, ring C is heterocyclic. In some embodiments, ring Cis pyrrolodine. In some embodiments, ring C is piperidine. In someembodiments, ring B is pyridyl , ring C is heterocyclic. In someembodiments, ring B is pyridyl, ring C is heterocycloalkyl, and R₁ isphenyl. In some embodiments, ring B is phenyl, ring C isheterocycloalkyl, and R₁ is phenyl.

In some embodiments, R₁ is heteroaryl. In some embodiments, ring C ispyrrolidine and R₁ is heteroaryl. In some embodiments, ring C ispyrrolidine and R₁ is pyrrozole. In some embodiments, ring B is pyridyl,ring C is pyrrolidine, and R_(l) is heteroaryl. In some embodiments,ring B is pyridyl, ring C is heterocycloalkyl, and R₁ is pyridyl..

In some embodiments, R₁ is cycloalkyl. In some embodiments, ring B ispyridyl and R₁ is cycloalkyl.

In some embodiments, the invention features a compound of formula lb-i:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;

Ring1C is a C6-C10 aryl ring , C3-C14 heteroaryl or heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently N, O, or S, ora C3-C10 cycloalkyl ring;

1 Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;

-   -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl        ; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-i exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is pyridyl, pyridine-2(1H)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,naphthalene, pyrrolidine, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, Y is 0. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, the invention features a compound of formula Ib-ii:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl        ; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-ii exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl or napthalene.

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,naphthalene, pyrrolidine, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, the invention features a compound of formulaIb-iii:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently N, O, or S,        and wherein one nitrogen on Ring C is the point of attachment to        the pyridine ring;    -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R2 groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula lb-iii exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is indole, piperidine, azepane, azetadine,indoline, isoindoline, or pyrrolidine.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole, and n is 1. Insome embodiments, R₁ is phenyl, pyridine, or pyrazole, n is 1, R₂ isamino or alkyl, and p is 0 or 1. In some embodiments, R₁ is phenyl,pyridine, or pyrazole, n is 1, R₃ is alkyl, such as methyl, and q is 1,2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-iii-1:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;    -   Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently N, O, or S,        and wherein one nitrogen on Ring C is the point of attachment to        the pyridine ring; R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6        alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6        alkenyl; C1-C6 alkynyl; (C1-C9 alkylene)-R₄ wherein up to four        CH₂ units are independently replaced with O, CO, S, SO, SO₂ or        NR; C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently O, S, N, or        NR; or C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy;C1C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH;CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula lb-iii-1 exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is pyridyl, pyridine-2(1H)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is indole, piperidine, azepane, azetadine,indoline, isoindoline, or pyrrolidine.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, -CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole, and n is 1. Insome embodiments, R₁ is phenyl, pyridine, or pyrazole, n is 1, R1 isamino or alkyl, and p is 0 or 1. In some embodiments, R₁ is phenyl,pyridine, or pyrazole, n is 1, R₃ is alkyl, such as methyl, and q is 1,2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-iii-2:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring;    -   Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently N, O, or S,        and wherein one nitrogen on Ring C is the point of attachment to        the pyridine ring;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ , or ═O            group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl        ; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1,2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-iii-2 exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl or naphthalene.

In some embodiments, ring C is indole, piperidine, azepane, azetadine,indoline, isoindoline, or pyrrolidine.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole, and n is 1. Insome embodiments, R₁ is phenyl, pyridine, or pyrazole, n is 1, R₂ isamino or alkyl, and p is 0 or 1. In some embodiments, R₁ is phenyl,pyridine, or pyrazole, n is 1, R₃ is alkyl, such as methyl, and q is 1,2, 3, or 4.

In some embodiments, the invention features a compound of formula Ib-iv:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently N, O, or S,        and wherein one nitrogen on Ring C is the point of attachment to        the pyridine ring;    -   R₁ is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy;C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH, units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-iv exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is indole, piperidine, azepane, azetadine,indoline, isoindoline, or pyrrolidine.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, R₁ is a phenyl, thiophene, pyridine, or pyrazole.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R1 is phenyl, pyridine, or pyrazole. In someembodiments, R₁ is phenyl, pyridine, or pyrazole, R₂ is amino or alkyl,and p is 0 or 1. In some embodiments, R₁ is phenyl, pyridine, orpyrazole, R₃ is alkyl, such as methyl, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-iv-1:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;    -   Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently N, O, or S,        and wherein one nitrogen on Ring C is the point of attachment to        the pyridine ring;    -   R₁ is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO_(I)R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, ring B is pyridyl, pyridine-2(1H)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, the compound of formula Ib-iv-1 exists as apharmaceutically acceptable prodrug.

In some embodiments, ring C is indole, piperidine, azepane, azetadine,indoline, isoindoline, or pyrrolidine.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, R₁ is a phenyl, thiophene, pyridine, or pyrazole.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole. In someembodiments, R₁ is phenyl, pyridine, or pyrazole, R, is amino or alkyl,and p is 0 or 1. In some embodiments, R₁ is phenyl, pyridine, orpyrazole, R₃ is alkyl, such as methyl, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-iv-2:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring;    -   Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein        anywhere from 1 to 4 ring atoms are independently N, O, or S,        and wherein one nitrogen on Ring C is the point of attachment to        the pyridine ring;    -   R₁ is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy;C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH, or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-iv-2 exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl or napthalene.

In some embodiments, ring C is indole, piperidine, azepane, azetadine,indoline, isoindoline, or pyrrolidine.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, R₁ is a phenyl, thiophene, pyridine, or pyrazole.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole. In someembodiments, R₁ is phenyl, pyridine, or pyrazole, R, is amino or alkyl,and p is 0 or 1. In some embodiments, R₁ is phenyl, pyridine, orpyrazole, R₃ is alkyl, such as methyl, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formula Ib-v:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-v exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole, and n is 1. Insome embodiments, R₁ is phenyl, pyridine, or pyrazole, n is 1, R₂ isamino or alkyl, and p is 0 or 1. In some embodiments, R₁ is phenyl,pyridine, or pyrazole, n is 1, R₃ is alkyl, such as methyl, and q is 1,2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-v-1:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;    -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-v-1 exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is pyridyl, pyridine-2(11-1)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, Cf₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole, and n is 1. Insome embodiments, R₁ is phenyl, pyridine, or pyrazole, n is 1, R₂ isamino or alkyl, and p is 0 or 1. In some embodiments, R₁ is phenyl,pyridine, or pyrazole, n is 1, R₃ is alkyl, such as methyl, and q is 1,2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-v-2:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring;    -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-v-2 exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl or napthalene.

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CR₂OCH₃, CN, CO?H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole, and n is 1. Insome embodiments, R₁ is phenyl, pyridine, or pyrazole, n is 1, R₂ isamino or alkyl, and p is 0 or 1. In some embodiments, R₁ is phenyl,pyridine, or pyrazole, n is 1, R₃ is alkyl, such as methyl, and q is 1,2, 3, or 4.

In some embodiments, the invention features a compound of formula Ib-vi:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   R₁ is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-vi exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, R₁ is a phenyl, thiophene, pyridine, or pyrazole.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole. In someembodiments, R₁ is phenyl, pyridine, or pyrazole, R₂ is amino or alkyl,and p is 0 or 1. In some embodiments, R₁ is phenyl, pyridine, orpyrazole, R₃ is alkyl, such as methyl, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-vi-1:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;    -   R₁ is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        Ci-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-vi-1 exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is pyridyl, pyridine-2(1H)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, R₁ is a phenyl, thiophene, pyridine, or pyrazole.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole. In someembodiments, R₁ is phenyl, pyridine, or pyrazole, R₂ is amino or alkyl,and p is 0 or 1. In some embodiments, R₁ is phenyl, pyridine, orpyrazole, R₃ is alkyl, such as methyl, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formulalb-vi-2:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring;    -   R₁ is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO_(I)R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-vi-2 exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl or napthalene.

In some embodiments, R₁ is a phenyl, thiophene, pyridine, or pyrazole.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₁ is phenyl, pyridine, or pyrazole. In someembodiments, R₁ is phenyl, pyridine, or pyrazole, R₂ is amino or alkyl,and p is 0 or 1. In some embodiments, R₁ is phenyl, pyridine, orpyrazole, R₃ is alkyl, such as methyl, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-vii:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;    -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   R₅ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   p is 0, 1, 2, or 3;    -   q is 0, 1, 2, 3, 4, or 5; and    -   r is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula lb-vii exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₅ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₅ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH₂C(CH₃)₃ OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃,CH(CH₃)₂, CCH, CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, r is 0. In some embodiments, r is 1. In someembodiments, r is 2. In some embodiments, r is 3. In some embodiments, ris 4. In some embodiments, r is 5.

In some embodiments, R₅ is halo or alkoxy. In some embodiments, R₂ isamino or alkyl, R₅ is halo or alkoxy, r is 1 or 2, and p is 0 or 1. Insome embodiments, R₅ is halo or alkoxy, R₃ is alkyl, such as methyl, ris 1 or 2, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formulaIb-viii:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;    -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   R₅ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   p is 0, 1,2,or 3;    -   q is 0, 1, 2, 3, 4, or 5; and    -   r is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-viii exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH,CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₅ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₅ is C1, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH₂C(CH₃)₃ OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃,CH(CH₃)₂, CCH, CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, r is 0. In some embodiments, r is 1. In someembodiments, r is 2. In some embodiments, r is 3. In some embodiments, ris 4. In some embodiments, r is 5.

In some embodiments, R₅ is halo or alkoxy. In some embodiments, R₂ isamino or alkyl, R₅ is halo or alkoxy, r is 1 or 2, and p is 0 or 1. Insome embodiments, R₅ is halo or alkoxy, R₃ is alkyl, such as methyl, ris 1 or 2, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formula Ib-ix:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;    -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   R₅ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;    -   is 0, 1, 2, or 3;    -   q is 0, 1, 2, 3, 4, or 5; and    -   r is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ib-ix exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein up to 4 ring atoms are independently O, S, N, or NR; or a (C1-C9alkylene)-R₄ wherein up to four CH₂ units are independently replacedwith O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, R₅ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₅ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH₂C(CH₃)₃ OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃,CH(CH₃)₂, CCH, CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, r is 0. In some embodiments, r is 1. In someembodiments, r is 2. In some embodiments, r is 3. In some embodiments, ris 4. In some embodiments, r is 5.

In some embodiments, R₅ is halo or alkoxy. In some embodiments, R₂ isamino or alkyl, R₅ is halo or alkoxy, r is 1 or 2, and p is 0 or 1. Insome embodiments, R₅ is halo or alkoxy, R₃ is alkyl, such as methyl, ris 1 or 2, and q is 1, 2, 3, or 4.

In some embodiments, the invention features a compound of formula Ic:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂. or ═O            group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ic exists as apharmaceutically acceptable prodrug.

In some embodinients, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, or dihydroindene.

In some embodiments, ring C a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, Y is 0. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example , R₂ isCl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH9CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, ring B is phenyl. In some embodiments, ring C isphenyl. In some embodiments, ring B and ring C are phenyl. In someembodiments, R₁ is halo. In some embodiments, R₁ is F. In someembodiments, R₁ is OCH₃. In some embodiments R₂ is amino. In someembodiments, R₃ is CH₃. In some embodiments, R₂ is amino and R₃ is CH₃.In some embodiments, Y is CH₃. In some embodiments, Y is O. In someembodiments, R₁ is F, R₂ is amino, R₃ is CH₃, and Y is CH₂. In someembodiments, Y is O. In some embodiments, R₁ is F, R₂ is amino, R₃ isCH₃, and Y is O.

In some embodiments, the invention features a compound of formula IC-i:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;

Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;

-   -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH;CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ic-i exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is pyridyl, pyridine-2(1H)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is,

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, or dihydroindene.

In some embodiments, ring C is is a group represented by thecorresponding moieties shown in the compounds of Table 1. For example,ring C is

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In other embodiments, the invention features a compound of formulaIC-ii:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Ic-ii exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl or napthalene.

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, Y is 0. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is R₁ isCH₃, Cl, F, CN, OCH₃, CF₃, CR2CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, the invention features a compound of formula Id:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or        heterocyclic ring wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   Y is CRR, CO, 0, 5, SO, SO₂, S(O)NH or NR;    -   R₁ is halo; CN; F₅S; SiR₃; OH; NRR; C1-C6 alkyl or fluoroalkyl;        C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl;        (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy;C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Id exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl, pyridyl, pyridine-2(1H)-one,pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, orquinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, or dihydroindene.

In some embodiments, ring C is is a group represented by thecorresponding moieties shown in the compounds of Table 1. For example,ring C is

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, ring B is phenyl. In some embodiments, ring B ispyridyl. In some embodiments, ring C is phenyl. In some embodiments,ring B and ring C are phenyl. In some embodiments, ring B is pyridyl andring C is phenyl. In some embodiments, Y is CH₂. In some embodiments, Yis O. In some embodiments, R2 is amino. In some embodiments, R2 is OH.In some embodiments, R₂ is OCH₃. In some embodiments, R₃ is CH₃. In someembodiments, R₂ is amino and R₃ is CH₃. In some embodiments, ring B ispyridyl, ring C is phenyl, and Y is CH₂. In some embodiments, ring B ispyridyl, ring C is phenyl, and Y is O.

In some embodiments, the invention features a compound of formula Id-i:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C3-C10 heteroaryl ring wherein anywhere from 1 to 4        ring atoms are independently O, S, N, or NR;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are independently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Id-i exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is pyridyl, pyridine-2(1H)-one, pyrazole,indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.

In some embodiments, ring B is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring B is

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, or dihydroindene.

In some embodiments, ring C is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, ring C is

In some embodiments, Y is 0. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF₂, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In some embodiments, the invention features a compound of formula Id-ii:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence:

-   -   Ring B is a C6-C10 aryl ring;    -   Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic        ring wherein anywhere from 1 to 4 ring atoms are indepednently        N, O, or S, or a C3-C10 cycloalkyl ring;    -   Y is CRR, CO, O, S, SO, SO₂, S(O)NH or NR;    -   R₁ is halo; CN; F_(S)S; SiR₃; OH; NRR; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; (C1-C9 alkylene)-R₄ wherein up to four CH₂ units are        independently replaced with O, CO, S, SO, SO₂ or NR; C6-C10        aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere        from 1 to 4 ring atoms are independently O, S, N, or NR; or        C3-C10 cycloalkyl;    -   R₂ is halo; OH; NRR; azide; CN; CO₂R; C1-C6 alkyl or        fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6        alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring        wherein anywhere from 1 to 4 ring atoms are independently O, S,        N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up        to four CH₂ units are independently replaced with O, CO, S, SO,        SO₂ or NR;        -   or two R₂ groups taken together may form a ═CH₂ or ═O group;    -   R₃ is halo; CN; CO₂R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl;        C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl;        C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂        units are independently replaced with O, CO, S, SO, SO₂ or NR;        -   or two R₃ groups taken together may form a ═CH₂ or ═O group;    -   R₄ is H; azide; CF₃; CHF₂; OR; CCH; CO₂R; OH; C6-C10 aryl,        C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to        4 ring atoms are independently O, S, N, or NR; C3-C10        cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO₂R;    -   R is independently H; OH; CO₂H; CO₂C1-C6 alkyl; C1-C6 alkyl;        C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or        heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are        independently O, S, N, or NR; or C3-C10 cycloalkyl;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound of formula Id-ii exists as apharmaceutically acceptable prodrug.

In some embodiments, ring B is phenyl or napthalene.

In some embodiments, ring C is phenyl, indole, cycloalkyl, pyridyl,pyrrolidine, naphthalene, or dihydroindene.

In some embodiments, ring C is is a group represented by thecorresponding moieties shown in the compounds of Table 1. For example,ring C is

In some embodiments, Y is O. In some embodiments, Y is CH₂. In someembodiments, Y is CH(C1-C6 alkyl). In some embodiments, Y is CH(CH₃). Insome embodiments, Y is CH(CH₂CH₃). In some embodiments, Y is NR, such asNH, N(C1-C6alkynyl), or N(C1-C6 alkyl).

In some embodiments, R₁ is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole,pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R₄ wherein up to fourCH₂ units are independently replaced with O, CO, S, SO, SO₂ or NR,wherein all rings are optionally substituted with one or more groupsselected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido, C3-C10heteroaryl, and C3-C10 heterocycloalkyl.

In some embodiments, R₁ is is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₁ is CH₃, Cl,F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂, OCH₂CH₂OCH₂CH₃,

In some embodiments, R₂ is halo, OH, CN, azide, amino, C1-C6 alkyl orfluoroalkyl, C1C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR; or a (C1-C9 alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR.

In some embodiments, R₂ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₂ is Cl, F,OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)CH₂CH₂CH₃, N(CH₃)CH₂CH₂CH₂CH₃,CH₃, CH₂OH, CH₂CH₃, CH₂CH₂CH₃, ═O, CH₃SO₂, CH₃SO₂NH, CF₃CONH, CH₃CONH,CH₃CON(CH₃), tBuOCONH, (CH₃)₂CHOCONH, CH(CH₃)₂, CHF,, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OCF₃, OCHF₂, OC(CH₃)₃, OCH₂CH₂tBu,NHCH(CH₃)(CH₂CH₂CH₃), OCH(CH₃)₂, NH(CH₂)₂O(CH₂)₂CH₃, C(O)CH₃, CH₂CH₂OH,CH₂NH₂, NH(CH₂)₂OH, N(CH₃)CH₂CH₂CH₂OCH₃, NHCH₂CH₂COOH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

In some embodiments, R₃ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR.

In some embodiments, R₃ is a group represented by the correspondingmoieties shown in the compounds of Table 1. For example, R₃ is Cl, I,deuterium, F, CN, CH₃, OH, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,OCH₂CH(CH₃)₂, OCH(CH₃)₂, CO₂H, CO₂NH₂, OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH,CH₂CONH₂, CO₂CH₃, —CH₂N(CH₃)₂, CO₂tBu, tBu, ═CH₂, ═O,

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, n is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2.

In another embodiment, the present invention provides compounds offormulas I to Id-ii that contain isotope-labelled forms thereof. Anisotope-labelled form of a compound of formulas I to Id-ii is identicalto this compound apart from the fact that one or more atoms of thecompound have been replaced by an atom or atoms having an atomic mass ormass number which differs from the atomic mass or mass number of theatom which usually occurs in greater natural abundance. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of formulas I to Id-ii by well-knownmethods include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound offormulas I to Id-ii, a prodrug thereof, or a pharmaceutically acceptablesalt of either which contains one or more of the above-mentionedisotopes and/or other iso-topes of other atoms is intended to be part ofthe present invention. An isotope-labelled compound of formulas I toId-ii can be used in a number of beneficial ways. For example, anisotope-labelled compound of formula I to In-i into which, for example,a radioisotope, such as ³H or ¹⁴C, has been incorporated is suitable formedicament and/or substrate tissue distribution assays. Theseradioisotopes, i.e. tritium (³H) and carbon-14 (¹⁴C), are particularlypreferred owing to simple preparation and excellent detectability.Incorporation of heavier isotopes, for example deuterium (²H), into acompound of formulas I to Id-ii has therapeutic advantages owing to thehigher metabolic stability of this isotope-labelled compound. Highermetabolic stability translates directly into an increased in vivohalf-life or lower dosages, which under most circumstances wouldrepresent a preferred embodiment of the present invention. Anisotope-labelled compound of formulas I to Id-ii can usually be preparedby carrying out the procedures disclosed in the synthesis schemes andthe related description, in the example part and in the preparation partin the present text, replacing a non-isotope-labelled reactant by areadily available isotope-labelled reactant.

Deuterium (²H) can also be incorporated into a compound of formulas I toId-ii for the purpose in order to manipulate the oxidative metabolism ofthe compound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus causes a reduction in the rate-limiting bond breakage. Ifthe bond breakage occurs in or in the vicinity of a saddle-point regionalong the coordinate of a multi-product reaction, the productdistribution ratios can be altered substantially. For explanation: ifdeuterium is bonded to a carbon atom at a non-exchangeable position,rate differences of k_(M)/k_(D)=2-7 are typical. If this rate differenceis successfully applied to a compound of formulas I to Id-ii that issusceptible to oxidation, the profile of this compound in vivo can bedrastically modified and result in improved pharmacokinetic properties.For a further discussion, see S. L. Harbeson and R. D. Tung, DeuteriumIn Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46,403-417, incorporated in its entirety herein by reference.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of formulas I to Id-ii with improved stabilitythrough resistance to such oxidative metabolism. Significantimprovements in the pharmacokinetic profiles of compounds of formulas Ito Id-ii are thereby obtained, and can be expressed quantitatively interms of increases in the in vivo half-life (t₁₁₂), concentration atmaximum therapeutic effect (C_(max)), area under the dose response curve(AUC), and bioavailability; and in terms of reduced clearance, dose andmaterials costs.

The following is intended to illustrate the above: a compound offormulas I to Id-ii which has multiple potential sites of attack foroxidative metabolism, for example benzc hydrogen atoms and hydrogenatoms bonded to a nitrogen atom, is prepared as a series of analogues inwhich various combinations of hydrogen atoms are replaced by deuteriumatoms, so that some, most or all of these hydrogen atoms have beenreplaced by deuterium atoms. Half-life determinations enable favourableand accurate determination of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of formulas I to Id-ii canalso be used to achieve a favorable modification of the metabolitespectrum of the starting compound in order to diminish or eliminateundesired toxic metabolites. For example, if a toxic metabolite arisesthrough oxidative carbon-hydrogen (C-H) bond cleavage, it can reasonablybe assumed that the deuterated analogue will greatly diminish oreliminate production of the unwanted metabolite, even if the particularoxidation is not a rate-determining step. Further information on thestate of the art with respect to deuterium-hydrogen exchange may befound, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990,Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res.14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, andJarman et al. Carcinogenesis 16(4), 683-688, 1993.

In some embodiments, the compound of formula I is selected from Table 1:

Lengthy table referenced here US20180185364A1-20180705-T00001 Pleaserefer to the end of the specification for access instructions.

In one embodiment, the present invention features any of the belownumerated embodiments.

-   1. In one embodiment, the present invention features a compound of    formula I:

or pharmaceutically acceptable salt thereof, wherein, independently foreach occurrence:

-   -   Ring A is a C6-C10 mono- or bicyclic aryl ring, or C5-C10 mono-        or bicyclic heteroaryl or heterocyclic ring wherein up to 4        carbon atoms may be replaced by O, S, N, or NR;    -   Ring B is a C6-C10 aryl ring or C5-C10 heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR;    -   Ring C is a C6-C10 mono- or bicyclic aryl ring , C4-C10 mono- or        bicyclic heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 carbon atoms may be replaced by N, O, or S, or a C3-C10        mono- or bicyclic cycloalkyl ring;    -   X is O or NR;    -   Y is CR₂, O, S, SO, SO₂, or NR;    -   Z is NR or CR₂;    -   R₁ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or        fluoroalkoxy, (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may        be replaced with O, CO, S, SO, SO₂ or NR; C6-C10 mono- or        bicyclic aryl, C5-C10 mono- or bicyclic heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        with O, S, N, or NR; or C3-C8 cycloalkyl, all four of which may        be substituted with halo, C1-C6 alkyl or fluoroalkyl, C1-C6        alkoxy or fluoroalkoxy, CN, CO₂H, amino, C5-C10 mono- or        bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR; C5-C10 mono- or bicyclic heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be        replaced with O, CO, S, SO, SO₂ or NR; or two R₁ along with the        atoms to which they are attached form a C5-C8 cyclic or        heterocyclic ring wherein up to 2 carbon atoms may be replaced        with 0, 5, or NR;    -   R₂ is halo, OH, amino, azide, CN, C1-C6 alkyl or fluoroalkyl,        C1-C6 alkoxy or fluoroalkoxy, C6-C10 mono- or bicyclic aryl,        C5-C10 mono- or bicyclic heteroaryl or heterocyclic ring wherein        up to 4 carbon atoms may be replaced with O, S, N, or NR, C3-C8        cycloalkyl; or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units        may be replaced with O, CO, S, SO, SO₂ or NR;    -   R₃ is halo, CN, CO₂R, C1-C6 alkyl, alkene, alkyne, or        fluoroalkyl; C1-C6 alkoxy, cycloalkoxy, or fluoroalkoxy; C6-C10        mono- or bicyclic aryl or C5-C10 mono- or bicyclic heteroaryl        wherein up to 4 carbon atoms may be replaced by O, S, N, or NR,        both of which may be substituted with halo, C1-C6 alkyl or        fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, CN, CO₂H, amino,        C5-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms        may be replaced by O, S, N, or NR; C5-C10 mono- or bicyclic        heterocycloalkyl wherein up to 4 carbon atoms may be replaced by        O, S, or NR; or or a (C1-C8 alkyl)-R₄ wherein up to three CH₂        units may be replaced with O, CO, S, SO, SO₂ or NR; or two R₃        may form a ═CH₂ or ═O group;    -   R₄ is H, CF₃, CO₂R, OH, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by 0, 5, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        N(R)₂, NRCOR, CON(R)₂, CN, halo, or SO₂R;    -   R is H, OH, C1-C6 alkyl, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by 0, 5, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5;    -   provided that the moieties containing ring B and ring C are        substituted at adjacent positions on ring A.

-   2. In another embodiment, the present invention features the    compound of embodiment 1, wherein ring A is a pyridyl, indole,    indoline, isoindoline, pyrazole, pyrimidine, phenyl, quinoline,    5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,    pyrrolidine, aza-indole, pyrrole, oxazole, pyrazine, triazole,    benzimidazole, indazole, or imidazole ring.

-   3. In another embodiment, the present invention features the    compound of embodiment 1 or 2, wherein ring A is selected from

-   4. In another embodiment, the present invention features the    compound of any of embodiments 1 to 3, wherein ring B is phenyl,    pyridyl, pyridine-2(1H)-one, pyrazole, indole, thiophene,    dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4(1H)-one,    pyrrolidinone, or quinoline.-   5. In another embodiment, the present invention features the    compound of any of embodiments 1 to 4, wherein ring B is selected    from

-   6. In another embodiment, the present invention features the    compound of any of embodiments 1 to 5, wherein ring C is phenyl,    indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, piperidine,    azetidine, or dihydroindene.-   7. In another embodiment, the present invention features the    compound of any of embodiments 1 to 6, wherein ring C is

-   8. In another embodiment, the present invention features the    compound of any of embodiments 1 to 7, wherein Y is O.-   9. In another embodiment, the present invention features the    compound of any of embodiments 1 to 7, wherein Y is CH₂.-   10. In another embodiment, the present invention features the    compound of any of embodiments 1 to 7, wherein Y is CH(C1-C6 alkyl).-   11. In another embodiment, the present invention features the    compound of any of embodiments 1 to 7, wherein Y is CH(CH₃).-   12. In another embodiment, the present invention features the    compound of any of embodiments 1 to 7, wherein Y is CH(CH₂CH₃).-   13. In another embodiment, the present invention features the    compound of any of embodiments 1 to 7, wherein Y is N(C1-C6 alkyl).-   14. In another embodiment, the present invention features the    compound of any of embodiments 1 to 7, wherein Y is N(CH₃).-   15. In another embodiment, the present invention features the    compound of any of embodiments 1 to 14, wherein R₁ is halo, CN,    C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl,    pyrimidine, indole, aza-indole, azetidine, or thiophene ring,    wherein all rings may be substituted with halo, C1-C6 alkyl, C1-C6    alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃,    CN, CO₂H, amino, amido, C5-C10 heteroaryl, C5-C10 heterocycloalkyl,    or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be replaced    with O, CO, S, SO, SO₂ or NR.-   16. In another embodiment, the present invention features the    compound of any of embodiments 1 to 15, wherein R₁ is selected from    CH₃, Cl, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

-   17. In another embodiment, the present invention features the    compound of any of embodiments 1 to 16, wherein R₂ is selected from    halo, OH, CN, azide, amino, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy    or fluoroalkoxy, C5-C10 mono- or bicyclic heterocyclic ring wherein    up to 4 carbon atoms may be replaced with O, S, N, or NR; or a    (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be replaced with    O, CO, S, SO, SO₂ or NR.-   18. In another embodiment, the present invention features the    compound of any of embodiments 1 to 17, wherein R₂ is selected from    Cl, F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃,    CH(CH₃)₂, CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH,    CH₂NH₂, NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂,    NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

or CO₂H.

-   19. In another embodiment, the present invention features the    compound of any of embodiments 1 to 18, wherein R₃ is selected from    halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or C5-C10 mono-    or bicyclic heteroaryl or heterocycloalkyl wherein up to 4 carbon    atoms may be replaced by O, S, N, or NR.-   20. In another embodiment, the present invention features the    compound of any of embodiments 1 to 19, wherein R₃ is selected from    Cl, F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃,    CH₂OCH₃, CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═CH₂, ═O,

-   21. In another embodiment, the present invention features the    compound of any of embodiments 1 to 20, wherein o is 0.-   22. In another embodiment, the present invention features the    compound of any of embodiments 1 to 20, wherein o is 1.-   23. In another embodiment, the present invention features the    compound of any of embodiments 1 to 20, wherein o is 2.-   24. In another embodiment, the present invention features the    compound of any of embodiments 1 to 23, wherein n is 0.-   25. In another embodiment, the present invention features the    compound of any of embodiments 1 to 23, wherein n is 1.-   26. In another embodiment, the present invention features the    compound of any of embodiments 1 to 23, wherein n is 2.-   27. In another embodiment, the present invention features the    compound of any of embodiments 1 to 26, wherein p is 0.-   28. In another embodiment, the present invention features the    compound of any of embodiments 1 to 26, wherein p is 1.-   29. In another embodiment, the present invention features the    compound of any of embodiments 1 to 26, wherein p is 2.-   30. In another embodiment, the present invention features the    compound of embodiment 1, wherein the compound is of formula Ia:

or pharmaceutically acceptable salt thereof, wherein, independently foreach occurrence:

-   -   Ring B is a C6-C10 aryl ring or C5-C10 heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR;    -   Ring C is a C6-C10 mono- or bicyclic aryl ring , C5-C10 mono- or        bicyclic heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 carbon atoms may be replaced by N, O, or S, or a C3-C10        mono- or bicyclic cycloalkyl ring;    -   X is O or NR;    -   Y is CR₂, O, S, SO, SO₂, or NR;    -   R₁ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or        fluoroalkoxy, (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may        be replaced with O, CO, S, SO, SO₂ or NR; C6-C10 mono- or        bicyclic aryl, C5-C10 mono- or bicyclic heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        with O, S, N, or NR; or C3-C8 cycloalkyl, all four of which may        be substituted with halo, C1-C6 alkyl or fluoroalkyl, C1-C6        alkoxy or fluoroalkoxy, CN, CO₂H, amino, C5-C10 mono- or        bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR; C5-C10 mono- or bicyclic heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be        replaced with O, CO, S, SO, SO₂ or NR; or two R₁ along with the        atoms to which they are attached form a C5-C8 cyclic or        heterocyclic ring wherein up to 2 carbon atoms may be replaced        with O, S, or NR;    -   R₂ is halo, OH, amino, azide, CN, C1-C6 alkyl or fluoroalkyl,        C1-C6 alkoxy or fluoroalkoxy, C6-C10 mono- or bicyclic aryl,        C5-C10 mono- or bicyclic heteroaryl or heterocyclic ring wherein        up to 4 carbon atoms may be replaced with O, S, N, or NR, C3-C8        cycloalkyl; or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units        may be replaced with O, CO, S, SO, SO₂ or NR;    -   R₃ is halo, CN, CO₂R, C1-C6 alkyl, alkene, alkyne, or        fluoroalkyl; C1-C6 alkoxy, cycloalkoxy, or fluoroalkoxy; C6-C10        mono- or bicyclic aryl or C5-C10 mono- or bicyclic heteroaryl        wherein up to 4 carbon atoms may be replaced by O, S, N, or NR,        both of which may be substituted with halo, C1-C6 alkyl or        fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, CN, CO₂H, amino,        C5-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms        may be replaced by O, S, N, or NR; C5-C10 mono- or bicyclic        heterocycloalkyl wherein up to 4 carbon atoms may be replaced by        O, S, or NR; or or a (C1-C8 alkyl)-R₄ wherein up to three CH₂        units may be replaced with O, CO, S, SO, SO₂ or NR; or two R₃        may form a ═CH₂ or ═O group;    -   R₄ is H, CF₃, CO₂R, OH, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by O, S, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        N(R)₂, NRCOR, CON(R)₂, CN, halo, or SO₂R;    -   R is H, OH, C1-C6 alkyl, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by O, S, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

-   31. In another embodiment, the present invention features a compound    of embodiment 30, wherein ring B is phenyl, pyridyl,    pyridine-2(1H)--one, pyrazole, indole, thiophene, dihydrobenzofuran,    pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or    quinoline.

-   32. In another embodiment, the present invention features a compound    of embodiment 30 or 31, wherein ring B is selected from

-   33. In another embodiment, the present invention features a compound    of any of embodiments 30 to 32, wherein ring C is phenyl, indole,    cycloalkyl, pyridyl, pyrrolidine, naphthalene, piperidine, or    dihydroindene.-   34. In another embodiment, the present invention features a compound    of any of embodiments 30 to 33, wherein ring C is

-   35. In another embodiment, the present invention features a compound    of any of embodiments 30 to 34, wherein Y is O.-   36. In another embodiment, the present invention features a compound    of any of embodiments 30 to 34, wherein Y is CH₂.-   37. In another embodiment, the present invention features a compound    of any of embodiments 30 to 34, wherein Y is CH(C1-C6 alkyl).-   38. The compound of claim 30, wherein Y is CH(CH₃).-   39. In another embodiment, the present invention features a compound    of any of embodiments 30 to 34, wherein Y is CH(CH₂CH₃).-   40. In another embodiment, the present invention features a compound    of any of embodiments 30 to 39, wherein R₁ is halo, CN, C1-C6 alkyl,    C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine,    indole, aza-indole, or thiophene ring, wherein all rings may be    substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl,    C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H, amino, amido,    C5-C10 heteroaryl, C5-C10 heterocycloalkyl, or a (C1-C8 alkyl)-R₄    wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂    or NR.-   41. In another embodiment, the present invention features a compound    of any of embodiments 30 to 40, wherein R₁ is selected from CH₃, Cl,    F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

-   42. In another embodiment, the present invention features a compound    of any of embodiments 30 to 41, wherein R₂ is selected from halo,    OH, CN, azide, amino, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or    fluoroalkoxy, C5-C10 mono- or bicyclic heterocyclic ring wherein up    to 4 carbon atoms may be replaced with O, S, N, or NR; or a (C1-C8    alkyl)-R₄ wherein up to three CH₂ units may be replaced with O, CO,    S, SO, SO₂ or NR.-   43. In another embodiment, the present invention features a compound    of any of embodiments 30 to 42, wherein R₂ is selected from Cl, F,    OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂,    CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂,    NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃,    NHCH(CH₃)₂, or CO₂H.

-   44. In another embodiment, the present invention features a compound    of any of embodiments 30 to 43, wherein R₃ is selected from halo,    CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or C5-C10 mono- or    bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by    O, S, N, or NR.-   45. In another embodiment, the present invention features a compound    of any of embodiments 30 to 44, wherein R₃ is selected from Cl, F,    CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃, CH₂OCH₃,    CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═CH₂, ═O,

-   46. In another embodiment, the present invention features a compound    of any of embodiments 30 to 45, wherein o is 0.-   47. In another embodiment, the present invention features a compound    of any of embodiments 30 to 45, wherein o is 1.-   48. In another embodiment, the present invention features a compound    of any of embodiments 30 to 47, wherein n is 0.-   49. In another embodiment, the present invention features a compound    of any of embodiments 30 to 47, wherein n is 1.-   50. In another embodiment, the present invention features a compound    of any of embodiments 30 to 47, wherein n is 2.-   51. In another embodiment, the present invention features a compound    of any of embodiments 30 to 50, wherein p is 0.-   52. In another embodiment, the present invention features a compound    of any of embodiments 30 to 50, wherein p is 1.-   53. In another embodiment, the present invention features a compound    of any of embodiments 30 to 50, wherein p is 2.-   54. In another embodiment, the present invention features a compound    of any of embodiments 30 to 53, wherein ring B is phenyl.-   55. In another embodiment, the present invention features a compound    of any of embodiments 30 to 54, wherein ring B and ring C are    phenyl.-   56. In another embodiment, the present invention features a compound    of embodiment 1, wherein the compound is of formula Ib:

or pharmaceutically acceptable salt thereof, wherein, independently foreach occurrence:

-   -   Ring B is a C6-C10 aryl ring or C5-C10 heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR;    -   Ring C is a C6-C10 mono- or bicyclic aryl ring , C5-C10 mono- or        bicyclic heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 carbon atoms may be replaced by N, O, or S, or a C3-C10        mono- or bicyclic cycloalkyl ring;    -   Y is CR₂, O, S, SO, SO₂, or NR;    -   R₁ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or        fluoroalkoxy, (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may        be replaced with O, CO, S, SO, SO₂ or NR; C6-C10 mono- or        bicyclic aryl, C5-C10 mono- or bicyclic heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        with O, S, N, or NR; or C3-C8 cycloalkyl, all four of which may        be substituted with halo, C1-C6 alkyl or fluoroalkyl, C1-C6        alkoxy or fluoroalkoxy, CN, CO₂H, amino, C5-C10 mono- or        bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR; C5-C10 mono- or bicyclic heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be        replaced with O, CO, S, SO, SO₂ or NR; or two R₁ along with the        atoms to which they are attached form a C5-C8 cyclic or        heterocyclic ring wherein up to 2 carbon atoms may be replaced        with O, S, or NR;    -   R₂ is halo, OH, amino, azide, CN, C1-C6 alkyl or fluoroalkyl,        C1-C6 alkoxy or fluoroalkoxy, C6-C10 mono- or bicyclic aryl,        C5-C10 mono- or bicyclic heteroaryl or heterocyclic ring wherein        up to 4 carbon atoms may be replaced with O, S, N, or NR, C3-C8        cycloalkyl; or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units        may be replaced with O, CO, S, SO, SO₂ or NR;    -   R₃ is halo, CN, CO₂R, C1-C6 alkyl, alkene, alkyne, or        fluoroalkyl; C1-C6 alkoxy, cycloalkoxy, or fluoroalkoxy; C6-C10        mono- or bicyclic aryl or C5-C10 mono- or bicyclic heteroaryl        wherein up to 4 carbon atoms may be replaced by O, S, N, or NR,        both of which may be substituted with halo, C1-C6 alkyl or        fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, CN, CO₂H, amino,        C5-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms        may be replaced by O, S, N, or NR; C5-C10 mono- or bicyclic        heterocycloalkyl wherein up to 4 carbon atoms may be replaced by        O, S, or NR; or or a (C1-C8 alkyl)-R₄ wherein up to three CH₂        units may be replaced with O, CO, S, SO, SO₂ or NR; or two R₃        may form a ═CH₂ or ═O group;    -   R₄ is H, CF₃, CO₂R, OH, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by O, S, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        N(R)₂, NRCOR, CON(R)₂, CN, halo, or SO₂R;    -   R is H, OH, C1-C6 alkyl, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by O, S, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

-   57. In another embodiment, the present invention features a compound    of embodiment 56, wherein ring B is phenyl, pyridyl,    pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran,    pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or    quinoline.

-   58. In another embodiment, the presnt invention features a compound    of embodiment 56 or 57, wherein ring B is selected from

-   59. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 58, wherein ring C is phenyl,    indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, or    dihydroindene.-   60. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 59, wherein ring C is

-   61. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 60, wherein Y is O.-   62. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 60, wherein Y is CH₂.-   63. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 60, wherein Y is CH(C1-C6 alkyl).-   64. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 60, wherein Y is CH(CH₃).-   65. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 60, wherein Y is CH(CH₂CH₃).-   66. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 65, wherein R₁ is halo, CN, C1-C6    alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl,    pyrimidine, indole, aza-indole, or thiophene ring, wherein all rings    may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6    fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H,    amino, amido, C5-C10 heteroaryl, C5-C10 heterocycloalkyl, or a    (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be replaced with    O, CO, S, SO, SO₂ or NR.-   67. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 66, wherein R₁ is selected from.    CH₃, CI, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

-   68. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 67, wherein R₂ is selected from    halo, OH, CN, azide, amino, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy    or fluoroalkoxy, C5-C10 mono- or bicyclic heterocyclic ring wherein    up to 4 carbon atoms may be replaced with O, S, N, or NR; or a    (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be replaced with    O, CO, S, SO, SO₂ or NR.-   69. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 68, wherein R₂ is selected from Cl,    F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂,    CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂,    NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃,    NHCH(CH₃)₂, or CO₂H.

-   70. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 69, wherein R₃ is selected from    halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or C5-C10 mono-    or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced    by O, S, N, or NR.-   71. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 70, wherein R₃ is selected from Cl,    F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃, CH₂OCH₃,    CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═CH₂, ═O,

-   72. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 71, wherein o is 0.-   73. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 71, wherein o is 1.-   74. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 71, wherein o is 2.-   75. in another embodiment, the present invention features a compound    of any one of embodiments 56 to 74, wherein n is 0.-   76. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 74, wherein n is 1.-   77. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 74, wherein n is 2.-   78. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 77, wherein p is 0.-   79. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 77, wherein p is 1.-   80. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 77, wherein p is 2.-   81. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 80, wherein ring B is pyridyl.-   82. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 81, wherein ring B is phenyl.-   83. In another embodiment, the present invention features a compound    of any one of embodiments 56 to 82, wherein ring B and ring C are    phenyl.-   84. In another embodiment, the present invention features a compound    of embodiment 1, wherein the compound is of formula Ic:

or pharmaceutically acceptable salt thereof, wherein, independently foreach occurrence:

-   -   Ring B is a C6-C10 aryl ring or C5-C10 heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR;    -   Ring C is a C6-C10 mono- or bicyclic aryl ring , C5-C10 mono- or        bicyclic heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 carbon atoms may be replaced by N, O, or S, or a C3-C10        mono- or bicyclic cycloalkyl ring;    -   Y is CR₂, O, S, SO, SO₂, or NR;    -   R₁ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or        fluoroalkoxy, (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may        be replaced with O, CO, S, SO, SO₂ or NR; C6-C10 mono- or        bicyclic aryl, C5-C10 mono- or bicyclic heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        with O, S, N, or NR; or C3-C8 cycloalkyl, all four of which may        be substituted with halo, C1-C6 alkyl or fluoroalkyl, C1-C6        alkoxy or fluoroalkoxy, CN, CO₂H, amino, C5-C10 mono- or        bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR; C5-C10 mono- or bicyclic heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be        replaced with O, CO, S, SO, SO₂ or NR; or two R₁ along with the        atoms to which they are attached form a C5-C8 cyclic or        heterocyclic ring wherein up to 2 carbon atoms may be replaced        with O, S, or NR;    -   R₂ is halo, OH, amino, azide, CN, C1-C6 alkyl or fluoroalkyl,        C1-C6 alkoxy or fluoroalkoxy, C6-C10 mono- or bicyclic aryl,        C5-C10 mono- or bicyclic heteroaryl or heterocyclic ring wherein        up to 4 carbon atoms may be replaced with O, S, N, or NR, C3-C8        cycloalkyl; or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units        may be replaced with O, CO, S, SO, SO₂ or NR;    -   R₃ is halo, CN, CO₂R, C1-C6 alkyl, alkene, alkyne, or        fluoroalkyl; C1-C6 alkoxy, cycloalkoxy, or fluoroalkoxy; C6-C10        mono- or bicyclic aryl or C5-C10 mono- or bicyclic heteroaryl        wherein up to 4 carbon atoms may be replaced by O, S, N, or NR,        both of which may be substituted with halo, C1-C6 alkyl or        fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, CN, CO₂H, amino,        C5-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms        may be replaced by O, S, N, or NR; C5-C10 mono- or bicyclic        heterocycloalkyl wherein up to 4 carbon atoms may be replaced by        O, S, or NR; or or a (C1-C8 alkyl)-R₄ wherein up to three CH₂        units may be replaced with O, CO, S, SO, SO₂ or NR; or two R₃        may form a ═CH₂ or ═O group;    -   R₄ is H, CF₃, CO₂R, OH, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by O, S, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        N(R)₂, NRCOR, CON(R)₂, CN, halo, or SO₂R;    -   R is H, OH, C1-C6 alkyl, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by O, S, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with 0, 5, or NR;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2,or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

-   85. In another embodiment, the present invention features a compound    of embodiment 84, wherein ring B is phenyl, pyridyl,    pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran,    pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or    quinoline.

-   86. In another embodiment, the present invention features a compound    of embodiment 84 or 85, wherein ring B is selected from

-   87. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 86, wherein ring C is phenyl,    indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, or    dihydroindene.-   88. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 87, wherein ring C is

-   89. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 88, wherein Y is O.-   90. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 88, wherein Y is CH₂.-   91. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 88, wherein Y is CH(C1-C6 alkyl).-   92. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 88, wherein Y is CH(CH₃).-   93. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 88, wherein Y is CH(CH₂CH₃).-   94. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 93, wherein R₁ is halo, CN, C1-C6    alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl,    pyrimidine, indole, aza-indole, or thiophene ring, wherein all rings    may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6    fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H,    amino, amido, C5-C10 heteroaryl, C5-C10 heterocycloalkyl, or a    (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be replaced with    O, CO, S, SO, SO₂ or NR.-   95. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 94, wherein R₁ is selected from CH₃,    Cl, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

-   96. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 95, wherein R₂ is selected from    halo, OH, CN, azide, amino, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy    or fluoroalkoxy, C5-C10 mono- or bicyclic heterocyclic ring wherein    up to 4 carbon atoms may be replaced with O, S, N, or NR; or a (C1C8    alkyl)-R₄ wherein up to three CH₂ units may be replaced with O, CO,    5, SO, SO₂ or NR.-   97. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 96, wherein R₂ is selected from Cl,    F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂,    CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂,    NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃,    NHCH(CH₃)₂, or CO₂H.

-   98. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 97, wherein R₃ is selected from    halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or C5-C10 mono-    or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced    by O, S, N, or NR.-   99. In another embodiment, the present invention features a compound    of any one of embodiments 84 to 98, wherein R₃ is selected from Cl,    F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃, CH₂OCH₃,    CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═CH₂, ═O,

-   100. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 99, wherein o is 0.-   101. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 99, wherein o is 1.-   102. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 99, wherein o is 2.-   103. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 102, wherein n is 0.-   104. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 102, wherein n is 1.-   105. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 102, wherein n is 2.-   106. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 105, wherein p is 0.-   107. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 105, wherein p is 1.-   108. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 105, wherein p is 2.-   109. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 108, wherein ring B is    phenyl.-   110. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 109, wherein ring C is    phenyl.-   111. In another embodiment, the present invention features a    compound of any one of embodiments 84 to 110, wherein ring B and    ring C are phenyl.-   112. In another embodiment, the present invention features a    compound of embodiment 1, wherein the compound is of formula Id:

or pharmaceutically acceptable salt thereof, wherein, independently foreach occurrence:

-   -   Ring B is a C6-C10 aryl ring or C5-C10 heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR;    -   Ring C is a C6-C10 mono- or bicyclic aryl ring , C5-C10 mono- or        bicyclic heteroaryl or heterocyclic ring wherein anywhere from 1        to 4 carbon atoms may be replaced by N, O, or S, or a C3-C10        mono- or bicyclic cycloalkyl ring;    -   Y is CR₂, O, S, SO, SO₂, or NR;    -   R₁ is halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or        fluoroalkoxy, (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may        be replaced with O, CO, S, SO, SO₂ or NR; C6-C10 mono- or        bicyclic aryl, C5-C10 mono- or bicyclic heteroaryl or        heterocyclic ring wherein up to 4 carbon atoms may be replaced        with O, S, N, or NR; or C3-C8 cycloalkyl, all four of which may        be substituted with halo, C1-C6 alkyl or fluoroalkyl, C1-C6        alkoxy or fluoroalkoxy, CN, CO₂H, amino, C5-C10 mono- or        bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced        by O, S, N, or NR; C5-C10 mono- or bicyclic heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be        replaced with O, CO, S, SO, SO₂ or NR; or two R₁ along with the        atoms to which they are attached form a C5-C8 cyclic or        heterocyclic ring wherein up to 2 carbon atoms may be replaced        with O, S, or NR;    -   R₂ is halo, OH, amino, azide, CN, C1-C6 alkyl or fluoroalkyl,        C1-C6 alkoxy or fluoroalkoxy, C6-C10 mono- or bicyclic aryl,        C5-C10 mono- or bicyclic heteroaryl or heterocyclic ring wherein        up to 4 carbon atoms may be replaced with O, S, N, or NR, C3-C8        cycloalkyl; or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units        may be replaced with O, CO, 5, SO, SO₂ or NR;    -   R₃ is halo, CN, CO₂R, C1-C6 alkyl, alkene, alkyne, or        fluoroalkyl; C1-C6 alkoxy, cycloalkoxy, or fluoroalkoxy; C6-C10        mono- or bicyclic aryl or C5-C10 mono- or bicyclic heteroaryl        wherein up to 4 carbon atoms may be replaced by O, S, N, or NR,        both of which may be substituted with halo, C1-C6 alkyl or        fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, CN, CO₂H, amino,        C5-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms        may be replaced by O, S, N, or NR; C5-C10 mono- or bicyclic        heterocycloalkyl wherein up to 4 carbon atoms may be replaced by        O, S, or NR; or or a (C1-C8 alkyl)-R₄ wherein up to three CH₂        units may be replaced with O, CO, S, SO, SO₂ or NR; or two R₃        may form a ═CH₂ or ═O group;    -   R₄ is H, CF₃, CO₂R, OH, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by O, S, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;        N(R)₂, NRCOR, CON(R)₂, CN, halo, or SO₂R;    -   R is H, OH, C1-C6 alkyl, C6-C10 mono- or bicyclic aryl, C5-C10        mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be        replaced by O, S, N, or NR; C3-C8 cycloalkyl or heterocycloalkyl        wherein up to 4 carbon atoms may be replaced with O, S, or NR;    -   n is 0, 1, 2 or 3;    -   o is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, 4, or 5.

-   113. In another embodiment, the present invention features a    compound of embodiment 112, wherein ring B is phenyl, pyridyl,    pyridine-2(1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran,    pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, or    quinoline.    -   114. In another embodiment, the present invention features a        compound of embodiment 112 or 113, wherein ring B is selected        from

-   115. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 114, wherein ring C is    phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, or    dihydroindene.-   116. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 115, wherein ring C is

-   117. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 116, wherein Y is O.-   118. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 116, wherein Y is CH₂.-   119. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 116, wherein Y is CH(C1-C6    alkyl).-   120. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 116, wherein Y is CH(CH₃).-   121. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 116, wherein Y is    CH(CH₂CH₃).-   122. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 121, wherein R₁ is halo,    CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl,    pyridyl, pyrimidine, indole, aza-indole, or thiophene ring, wherein    all rings may be substituted with halo, C1-C6 alkyl, CI-C6 alkoxy,    C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H,    amino, amido, C5-C10 heteroaryl, C5-C10 heterocycloalkyl, or a    (C1-C8 alkyl)-R₄ wherein up to three CH₂ units may be replaced with    O, CO, S, SO, SO₂ or NR.-   123. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 122, wherein R₁ is    selected from CH₃, Cl, F, CN, OCH₃, CF₃, CH₂CH₃, tBu, CH(CH₃)₂,

-   124. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 123, wherein R₂ is    selected from halo, OH, CN, azide, amino, C1-C6 alkyl or    fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C5-C10 mono- or bicyclic    heterocyclic ring wherein up to 4 carbon atoms may be replaced with    O, S, N, or NR; or a (C1-C8 alkyl)-R₄ wherein up to three CH₂ units    may be replaced with O, CO, S, SO, SO₂ or NR.-   125. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 124, wherein R₂ is    selected from Cl, F, OH, CN, N₃, NH₂, NH(CH₃), N(CH₃)₂, CH₃, CH₂OH,    CH₂CH₃, CH(CH₃)₂, CHF₂, OCH₃, OCF₃, OCHF₂, OCH(CH₃)₂, C(O)CH₃,    CH₂CH₂OH, CH₂NH₂, NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂NH₂,    NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

or CO₂H.

-   126. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 125, wherein R₃ is    selected from halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or    C5-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may    be replaced by O, S, N, or NR.-   127. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 126, wherein R₃ is    selected from CI, F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃,    OCH₂CH₃, CH₂OCH₃, CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═CH₂, ═O,

-   128. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 127, wherein o is 0.-   129. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 127, wherein o is 1.-   130. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 127, wherein o is 2.-   131. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 130, wherein n is 0.-   132. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 130, wherein n is 1.-   133. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 130, wherein n is 2.-   134. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 133, wherein p is 0.-   135. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 133, wherein p is 1.-   136. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 133, wherein p is 2.-   137. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 136, wherein ring B is    phenyl.-   138. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 137, wherein ring B is    pyridyl.-   139. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 138, wherein ring C is    phenyl.-   140. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 139, wherein ring B and    ring C are phenyl.-   141. In another embodiment, the present invention features a    compound of any one of embodiments 112 to 140, wherein ring B is    pyridyl and ring C is phenyl.-   142. In another embodiment, the present invention features a    compound of embodiment 1, wherein the compound is selected from    Table 1.-   143. In another embodiment, the present invention features a    pharmaceutical composition comprising the compound of any one of    embodiments 1 to 142 and a pharmaceutically acceptable carrier.-   144. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 143, further comprising one    or more additional therapeutic agent(s).-   145. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agent is selected from a mucolytic agent,    bronchodialator, an antibiotic, an anti-infective agent, a CFTR    modulator, or an anti-inflammatory agent.-   146. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agent is a CFTR modulator.-   147. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agent is a CFTR corrector.-   148. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agent is

or pharmaceutically acceptable salt thereof.

149. In another embodiment, the present invention features thepharmaceutical composition of embodiment 144, wherein the additionaltherapeutic agent is

or pharmaceutically acceptable salt thereof.

-   150. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agent is

or pharmaceutically acceptable salt thereof.

-   151. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agent is a CFTR potentiator.-   152. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agent is

or pharmaceutically acceptable salt thereof.

-   153. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agents are a CFTR corrector and a CFTR potentiator.-   154. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agents are

or pharmaceutically acceptable salts thereof.

-   155. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agents are

or pharmaceutically acceptable salts thereof.

-   156. In another embodiment, the present invention features the    pharmaceutical composition of embodiment 144, wherein the additional    therapeutic agents are

or pharmaceutically acceptable salts thereof.

-   157. In another embodiment, the present invention features a method    of treating cystic fibrosis in a patient comprising administering to    the patient an effective amount of the compound of any one of    embodiments 1 to 142 or the pharmaceutical composition of any one of    embodiments 143 to 156.-   158. In another embodiment, the present invention features the    method of embodiment 157, further comprising administering to the    patient one or more additional therapeutic agent(s) prior to,    concurrent with, or subsequent to the compound of any one of    embodiments 1 to 137 or the pharmaceutical composition of any one of    embodiments 138 to 151.-   159. In another embodiment, the present invention features the    method of embodiment 158, wherein the additional therapeutic agent    is selected from a mucolytic agent, bronchodialator, an antibiotic,    an anti-infective agent, a CFTR modulator, or an anti-inflammatory    agent.-   160. In another embodiment, the present invention features the    method of embodiment 158, wherein the additional therapeutic agent    is a CFTR modulator.-   161. In another embodiment, the present invention features the    method of embodiment 158, wherein the additional therapeutic agent    is a CFTR corrector.-   162. In another embodiment, the present invention features the    method of embodiment 158, wherein the additional therapeutic agent    is

or a pharmaceutically acceptable salt thereof.

-   163. In another embodiment, the present invention features the    method of embodiment 158, wherein the additional therapeutic agent    is

or a pharmaceutically acceptable salt thereof.

-   164. In another embodiment, the present invention features the    method of embodiment 158, wherein the additional therapeutic agent    is

or a pharmaceutically acceptable salt thereof.

-   165. In another embodiment, the present invention features the    method of embodiment 158, wherein the additional therapeutic agent    is a CFTR potentiator.-   166. In another embodiment, the present invention features the    method of embodiment 158, wherein the additional therapeutic agent    is

or a pharmaceutically acceptable salt thereof.

-   167. In another embodiment, the present invention features the    method of any one of embodiments 157 to 166, wherein the patient is    homozygous in the F508del CFTR mutation.-   168. In another embodiment, the present invention features the    method of any one of embodiments 157 to 166, wherein the patient is    heterozygous in the F508del CFTR mutation.-   169. In another embodiment, the present invention features a kit    comprising the compound of any one of embodiments 1 to 142 or the    pharmaceutical composition of any one of embodiments 143 to 156, and    instructions for use therof.-   170. In another embodiment, the present invention features the kit    of embodiment 169, further comprising one or more additional    therapeutic agent(s).-   171. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agent is    selected from a mucolytic agent, bronchodialator, an antibiotic, an    anti-infective agent, a CFTR modulator, or an anti-inflammatory    agent.-   172. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agent is a    CFTR modulator.-   173. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agent is a    CFTR corrector.-   174. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

-   175. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

-   176. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

-   177. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agent is a    CFTR potentiator.-   178. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

-   179. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agents are a    CFTR corrector and a CFTR potentiator.-   180. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

-   181. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

-   182. In another embodiment, the present invention features the kit    of embodiment 170, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

-   183. In another embodiment, the present invention features the kit    of any one of embodiments 169 to 182, wherein the compound of any    one of embodiments 1 to 142 or the pharmaceutical composition of any    one of embodiments 143 to 156 and the one or more additional    therapeutic agent(s) are in separate containers.-   184. In another embodiment, the present invention features the kit    of any one of embodiments 169 to 182, wherein the compound of any    one of embodiments 1 to 142 or the pharmaceutical composition of any    one of embodiments 143 to 156 and the one or more additional    therapeutic agent(s) are in the same container.-   185. In another embodiment, the present invention features the kit    of embodiment 183 or 184, wherein the container is a bottle, vial,    or blister pack, or combination thereof.

Methods of Preparing Compounds of Formula I

Compounds of the invention may be prepared by known methods and asillustrated in Schemes I-XX1. Ring A, B, C and R, R₁, R₂, R₃, R₄, X Y, Zand n, o, p, q are as defined in the Specification unless notedotherwise below for each individual scheme.

Pharmaceutically Acceptable Salts and Prodrugs of Compounds of FormulasI-Id

It will also be appreciated that certain compounds of the compositionsof the present invention can exist in free form for treatment, or whereappropriate, as a pharmaceutically acceptable derivative or a prodrugthereof. According to the present invention, a pharmaceuticallyacceptable derivative or a prodrug includes, but is not limited to,pharmaceutically acceptable salts, esters, salts of such esters, or anyother adduct or derivative which upon administration to a patient inneed is capable of providing, directly or indirectly, a compound asotherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt”’ refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quatemization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

Pharmaceutical Compositions Pharmaceutically Acceptable Vehicle,Adjuvant, or Carrier

In one aspect, the present invention features a pharmaceuticalcomposition comprising a compound of formula I or pharmaceuticallyacceptable salt or prodrug thereof, and a pharmaceutically acceptablevehicle, adjuvant, or carrier.

As described above, the pharmaceutical compositions of the presentinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington: The Science andPractice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, LippincottWilliams & Wilkins, Philadelphia, and Encyclopedia of PharmaceuticalTechnology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, MarcelDekker, N.Y., the contents of each of which is incorporated by referenceherein, disclose various carriers used in formulating pharmaceuticallyacceptable compositions and known techniques for the preparationthereof. Except insofar as any conventional carrier medium isincompatible with the compounds of the invention, such as by producingany undesirable biological effect or otherwise interacting in adeleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Additional Therapeutic Agent(s)

In another embodiment, the pharmaceutical compositions of the presentinvention further comprise one or more additional therapeutic agent(s).In one embodiment, the additional therapeutic agent is a CFTR modulator.In one embodiment, the additional therapeutic agent is a CFTR corrector.In one embodiment, the additional therapeutic agent is a CFTRpotentiator. In another embodiment, the pharmaceutical compositioncomprises a compound of formula I and one or more of the followingadditional therapeutic agents.

In another embodiment, the additional therapeutic agent is selectedfrom:

3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or a pharmaceutically acceptable salt thereof; or

4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of formula I, or pharmaceuticallyacceptable salt thereof and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of Table 1, or pharmaceuticallyacceptable salt thereof and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of formula I, or pharmaceuticallyacceptable salt thereof and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of Table 1, or pharmaceuticallyacceptable salt thereof and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of formula I, or pharmaceuticallyacceptable salt thereof and4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxarnido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of Table 1, or pharmaceuticallyacceptable salt thereof and4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of formula I, or pharmaceuticallyacceptable salt thereof; and a compound selected from3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of Table 1, or pharmaceuticallyacceptable salt thereof; and a compound selected from3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropart-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[-3-phenyl-1-piperidyl]pyridine-3-carboxamide(Compound 233), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 238), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 318), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 196), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydoxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 337), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 368), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 182), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1356), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 172), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 639), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 300), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1660), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 234), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-tert-butyl-N-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 262), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 207), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 320), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 353), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 171), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide(Compound 114), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide(Compound 321), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 15), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(4-aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 265), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 164), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-tert-butyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 214), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(7-fluoro-1,3-benzodioxol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 345), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 8), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 110), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 281), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 351), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 197), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(4-chloro-3-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 136), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises2-(2,5-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide(Compound 307), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 279), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(4-chloro-3-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 72), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(benzenesulfonyl)-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 45), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminophenyl)sulfonyl-4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 299), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-methoxy-3-pyridyl)sulfonyl]-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 365), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 361), or pharmaceutically acceptable salt thereof; and acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable saltsthereof.

In one embodiment, the above recited pharmaceutical compositions containa pharmaceutically acceptable prodrug of the compound of the presentinvention.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of formula I, or pharmaceuticallyacceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of Table 1, or pharmaceuticallyacceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[-3-phenyl-1-piperidyl]pyridine-3-carboxamide(Compound 233), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[4][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 238), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 318), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 196), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 337), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl[-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl[pyridine-3-carboxamide(Compound 368), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 182), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1356), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3[dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 172), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl[-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 639), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 300), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1660), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 234), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-tert-butyl-N-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 262), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 207), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 320), or pharmaceutically acceptable salt thereof; and3-(6-(1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 353), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 171), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide(Compound 114), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide(Compound 321), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 15), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 265), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 164), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-tert-butyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 214), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(7-fluoro-1,3-benzodioxol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 345), or pharmaceutically acceptable salt thereof; and3-(6(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 8), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl[pyrazole-3-carboxamide(Compound 110), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl[-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 281), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 351), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3[dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 197), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3[dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(4-chloro-3-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 136), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises2-(2,5-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide(Compound 307), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 279), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(4-chloro-3-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 72), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(benzenesulfonyl)-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 45), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminophenyl)sulfonyl-4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 299), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-methoxy-3-pyridyl)sulfonyl]-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 365), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 361), or pharmaceutically acceptable salt thereof; and3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In one embodiment, the above recited pharmaceutical compositions containa pharmaceutically acceptable prodrug of the compound of the presentinvention.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of formula I, or pharmaceuticallyacceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of Table 1, or pharmaceuticallyacceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[-3-phenyl-1-piperidyl]pyridine-3-carboxamide(Compound 233), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 238), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 318), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 196), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 337), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 368), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 182), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1356), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 172), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 639), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 300), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1660), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 234), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-tert-butyl-N-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 262), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises N -[(6amino-2-pyridyl)sulfonyl]-6-(4-chloro-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide (Compound 207), or pharmaceuticallyacceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 320), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 353), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 171), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide(Compound 114), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide(Compound 321), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 15), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(4-aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 265), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 164), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-tert-butyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 214), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(7-fluoro-1,3-benzodioxol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 345), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 8), or pharmaceutically acceptable salt thereof; and (R)1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 110), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 281), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 351), or pharmaceutically acceptable salt thereof; and (R)1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises.N-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 197), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(4-chloro-3-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 136), or pharmaceutically acceptable salt thereof; and (R)1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises2-(2,5-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide(Compound 307), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 279), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(4-chloro-3-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 72), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(benzenesulfonyl)-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 45), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminophenyl)sulfonyl-4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 299), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-methoxy-3-pyridyl)sulfonyl]-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 365), or pharmaceutically acceptable salt thereof; and(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 361), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of formula I, or pharmaceuticallyacceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a compound of Table 1, or pharmaceuticallyacceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[-3-phenyl-1-piperidyl]pyridine-3-carboxamide(Compound 233), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 238), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 318), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 196), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 337), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 368), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 182), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1356), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 172), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 639), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 300), or pharmaceutically acceptable salt thereof; and.N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1660), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 234), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-tert-butyl-N-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 262), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 207), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 320), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 353), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 171), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide(Compound 114), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide(Compound 321), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 15), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(4-aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 265), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 164), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-tert-butyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 214), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(7-fluoro-1,3-benzodioxol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 345), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 8), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 110), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 281), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluora-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 351), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminopyrazin-2-yl)sulfonyl]-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 197), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(4-chloro-3-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 136), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises2-(2,5-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide(Compound 307), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 279), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(4-chloro-3-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 72), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(benzenesulfonyl)-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 45), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-(3-aminophenyl)sulfonyl-4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 299), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(2-methoxy-3-pyridyl)sulfonyl]-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 365), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprisesN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 361), or pharmaceutically acceptable salt thereof; andN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the additional therapeutic agent is selected fromthe following table:

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

In one embodiment, the additional therapeutic agent is selected from thefollowing table:

Compounds disclosed in U.S. Pat. No. 7,407,976 (Col 13, ln 35- col 66,ln 67; Compounds 1-100 in Table 1 at col 67, ln 1-col 127, ln 42)Compounds disclosed in U.S. Pat. No. 7,645,789 (Col 16, ln 52-col 50, ln22; Compounds 1-322 in Table 1 at col 50, ln 24-col 167, ln 42)Compounds disclosedin U.S. Pat. No. 7,659,268 (Col 16, ln 20-col 70, ln52; Compounds 1-528 in Table 1 at col 70, ln 53-col 331, ln 34)Compounds disclosed in U.S. Pat. No. 7,671,221 (Col 16, ln 12-col 54, ln48; Compounds 1-1216 in Table 1 at col 54, ln 49-col 699, ln 27)Compounds disclosed in U.S. Pat. No. 7,691,902 (Col 16, ln 11-col 54, ln29; Compounds 1-959 in Table 1 at col 54, ln 29-col 683, ln 44)Compounds disclosed in U.S. Pat. No. 7,741,321 (Col 16, ln 25-col 72, ln17; Compounds 1-422 in Table 1 at col 72, ln 20-col 279, ln 15)Compounds disclosed in U.S. Pat. No. 7,754,739 (Col 16, ln 1-col 22, ln47; Compounds 1-2 in Table 1 at col 18, ln 26-65) Compounds disclosed inU.S. Pat. No. 7,776,905 (Col 16, ln 23-col 38, ln 40; Compounds 1-306 inTable 1 at col 38, ln 45-col 96, ln 40) Compounds disclosed in U.S. Pat.No. 7,973,169 (Col 9, ln 16-col 40, ln 40; Compounds 1-289 in Table 1 atcol. 40, ln 41-col 289, ln 39) Compounds disclosed in U.S. Pat. No.7,977,322 (Col 6, ln 26-col 37, ln 47; Compounds 1-498 in Table 1 at col37, ln 50-col 141, ln 40) Compounds disclosed in U.S. Pat. No. 7,999,113(Col 6, ln 13-col 10, ln 67; Compounds 1-13 in Table 1 at col 11, ln5-col 13, ln 65) Compounds disclosed in U.S. Pat. No. 8,227,615 (Col 6,ln 10-col 29, ln 66; Compounds 1-78 in Table 1 at col 30, ln 1-col 46,ln 48) Compounds disclosed in U.S. Pat. No. 8,299,099 (Col 6, ln 10-col34, ln 18; Compounds 1-47 in Table 1 at col 34, ln 20-col 42, ln 35)Compounds disclosed in US Published Application No. 2006-0052358(Paragraphs [0034]- [0056]; [0077]-[0240]; Compounds 1-320 in Table 1 atparagraph [0241]) Compounds disclosed in US Published Application No.2009-0143381 (Paragraphs [0102]- [0263]; Compounds 1-28 in Table 1 atparagraph [0264]) Compounds disclosed in US Published Application No.2009-0170905 (Paragraphs [0012]- [0013]; [0030]-[0051]) Compoundsdisclosed in US Published Application No. 2009-0253736 (Paragraphs[0031]- [0162]; Compounds 1-15 in Table 1 at paragraph [0163]) Compoundsdisclosed in US Published Application No. 2011-0263654 (Paragraphs[0012]- [0013]; [0066]-[0141]) Compounds disclosed in US PublishedApplication No. 2011-0251253 (Paragraphs [0012]- [0013]; [0054]-[0079])Compounds disclosed in PCT application WO2008141119 (Paragraphs[0100]-[0339]; Compounds 1-117 in Table 1 at paragraph [0340]) Compoundsdisclosed in U.S. application Ser. No. 11/047,361 Compounds disclosed inUS Published Application No. 2013-0116238 (Paragraphs [0028]- [0044];[0117]-[0128]), or combinations thereof.

In another embodiment, the additional therapeutic agent is selected from

N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; or

N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide,or pharmaceutically acceptable salt thereof

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b) a compoundselected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound selected fromN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamideorN-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b) a compound selectedfrom 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound selected fromN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamideorN-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the additional therapeutic agent is selected fromthe following table:

Compounds disclosed in US Published Application No. 2005-0113423(Paragraph [00146]; Compounds IA-1-IA-136 and Compounds I-1-I-21 inTables 1 and 2 at paragraphs [0391]- [0392]) Compounds disclosed in USPublished Application No. 2005-0059687 (Paragraphs [00100]-[00101];Compounds 1-405 in Table 1 at paragraph [0169]) Compounds 1-108disclosed in U.S. Pat. No. 7,598,412 (Col 22, ln 14-col 79, ln 20;Table 1) Compounds 1-485 disclosed in U.S. Pat. No. 7,495,103 (Col 51,ln 1-col 63, ln 43; Table 1) Compounds 1-718 disclosed in U.S. Pat. No.8,354,427 (Col 51, ln 3-col 71, ln 46; Table 1) Compounds 1-233disclosed in US Published Application No. 2007-0105833 (Paragraph[00145]; Table 1) Compounds 1-26 disclosed in U.S. Pat. No. 8,242,149(Col 46, ln 47-col 57, ln 37; Table 1) Compounds 1-18 disclosed in U.S.Pat. No. 8,314,256 (Col 21, ln 1-col 26, ln 19) Compounds 1-14 disclosedin U.S. Pat. No. 8,399,479 (Col 36, ln 20-col 38, ln 40; Table 1)Compounds 1-18 disclosed in U.S. Pat. No. 8,188,283 (Col 38, ln 43-col43, ln 36; Table 1) Compounds 1-16 disclosed in US Published ApplicationNo. 2010-0249180 (Paragraph [0173]; Table 1) Compounds 1-19 disclosed inUS Published Application No. 2011-0008259 (Paragraph [0172]; Table 1)Compounds 1-129 disclosed in U.S. Pat. No. 8,367,660 (Col 57, ln 31-col81, ln 24; Table1)

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b) a compoundselected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound selected fromN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamideorN-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b) a compound selectedfrom 3-(6-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound selected fromN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamideorN-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b) a compoundselected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound selected from certainflavones and isoflavones, such as genistein, which are capable ofstimulating CFTR-mediated chloride transport in epithelial tissues in acyclic-AMP independent manner (See U.S. Pat. No. 6,329,422, incorporatedherein by reference in its entirety); phenylglycine-01(2-[(2-1H-indol-3-yl-acetyl)-methylamino]-N-(4-isopropylphenyl)-2-phenylacetamide);felodipine (Ethyl methyl4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate);sulfonamide SF-01(6-(ethylphenylsulfamoyl)-4-oxo-1,4-dihydroquinoline-3-carboxc acidcycloheptylamide); and UCCF-152(3-[2-(benzyloxy)phenyl]-5-(chloromethyl)isoxazole).

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[-3-phenyl-1-piperidyl]pyridine-3-carboxamide(Compound 233), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 238), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 318), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 196), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 337), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 368), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 182), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1356), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 172), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 639), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 300), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1660), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 234), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-tert-butyl-N-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 262), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 207), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 320), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 353), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 171), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide(Compound 114), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide(Compound 321), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 15), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(4-aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 265), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 164), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-tert-butyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 214), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(7-fluoro-1,3-benzodioxol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 345), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 8), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 110), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 281), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 351), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 197), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(4-chloro-3-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 136), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)2-(2,5-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide(Compound 307), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 279), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(4-chloro-3-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 72), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(benzenesulfonyl)-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 45), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(3-aminophenyl)sulfonyl-4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 299), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a) N-[(2-methoxy-3-pyridyl)sulfonyl]-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 365), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 361), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, orpharmaceutically acceptable salt thereof.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[-3-phenyl-1-piperidyl]pyridine-3-carboxamide(Compound 233), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c) (R)1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a) N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 238), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 318), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 196), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 337), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 368), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 182), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1356), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 172), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 639), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 300), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 1660), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 234), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-tert-butyl-N-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 262), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 207), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 320), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 353), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 171), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide(Compound 114), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl[-6-(6-isopropoxy-3-pyridyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide(Compound 321), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 15), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3[dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(4-aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 265), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3[dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 164), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3[dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-tert-butyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 214), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(7-fluoro-1,3-benzodioxol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 345), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 8), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 110), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 281), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 351), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 197), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(4-chloro-3-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 136), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)2-(2,5-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide(Compound 307), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 279), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(4-chloro-3-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 72), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(benzenesulfonyl)-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 45), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-(3-aminophenyl)sulfonyl-4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 299), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(2-methoxy-3-pyridyl)sulfonyl]-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 365), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a)N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 361), or pharmaceutically acceptable salt thereof; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide,or pharmaceutically acceptable salt thereof; and c)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or pharmaceutically acceptable salt thereof.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the present invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b) a compoundselected from 3(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) an additional CFTR corrector.

In another embodiment, the present invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b) a compound selectedfrom 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) an additional CFTR corrector.

In another embodiment, the above recited pharmaceutical compositioncontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In another embodiment, the additional CFTR corrector from above is(N-(2-(5-chloro-2-methoxy-phenylamino)-4′-methyl-]4,5′]bithiazolyl-2′-yl)-benzamide(corr-4a). In another embodiment, the additional CFTR corrector is acompound disclosed in published International Patent ApplicationWO2014081820, incorporated herein in its entirety by reference.

In another embodiment, the present invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamideorN-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide;and a CFTR corrector selected from(N-(2-(5-chloro-2-methoxy-phenylamino)-4′-methyl-]4,5′]bithiazolyl-2′-yl)-benzamide(corr-4a), a compound disclosed in published International PatentApplication WO2014081820, incorporated herein in its entirety byreference, a compound disclosed in Published International PatentApplication No. WO2014086687, or a compound disclosed in U.S. Pat. No.8,247,436 or 8,476,269; U.S. patent application Ser. No. 13/923,349; orPublished International Patent Application No: WO2011113894,WO2013038373, WO2013038378, WO2013038381, WO2013038386, or WO2013038390;all US patents, US patent applications, and published internationalpatent applications are hereby incorporated in their entirety byreference.

In another embodiment, the present invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b) a compoundselected from certain flavones and isoflavones, such as genistein, whichare capable of stimulating CFTR-mediated chloride transport inepithelial tissues in a cyclic-AMP independent manner (See U.S. Pat. No.6,329,422, incorporated herein by reference in its entirety);phenylglycine-01(24(2-1H-indol-3-yl-acetyl)-methylamino]-N-(4-isopropylphenyl)-2-phenylacetamide);felodipine (Ethyl methyl4(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate);sulfonamide SF-01(6-(ethylphenylsulfamoyl)-4-oxo-1,4-dihydroquinoline-3-carboxc acidcycloheptylamide); and UCCF-152(3-[2-(benzyloxy)phenyl]-5-(chloromethyl)isoxazole); and c) a CFTRcorrector selected from(N-(2-(5-chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]bithiazolyl-2′-yl)-benzamide(corr-4a), a compound disclosed in published. International PatentApplication WO2014081820, incorporated herein in its entirety byreference, or a compound disclosed in US Pat. Nos. 8,247,436 or8,476,269; U.S. patent application Ser. No. 13/923,349; or PublishedInternational Patent Application No: WO2011113894, WO2013038373,WO2013038378, WO2013038381, WO2013038386, or WO2013038390; all USpatents, US patent applications, and published international patentapplications are hereby incorporated in their entirety by reference.

In another embodiment, the present invention features the pharmaceuticalcomposition described above comprising a) a compound of formula I; b) acompound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid,(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide,or4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) an additional CFTR corrector, suchas those, for example, specifically listed above; and further comprisingd) a CFTR potentiator.

In another embodiment, the CFTR potentiator from above isN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamideorN-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.In another embodiment, the CFTR potentiator from above isN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the CFTR potentiator from above is selected fromcertain flavones and isoflavones, such as genistein, which are capableof stimulating CFTR-mediated chloride transport in epithelial tissues ina cyclic-AMP independent manner (See U.S. Pat. No. 6,329,422,incorporated herein by reference in its entirety); phenylglycine-01(2-[(2-1H-indol-3-yl-acetyl)-methylamino]-N-(4-isopropylphenyl)-2-phenylacetamide);felodipine (Ethyl methyl4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate);sulfonamide SF-01(6-(ethylphenylsulfamoyl)-4-oxo-1,4-dihydroquinoline-3-carboxc acidcycloheptylamide); and UCCF-152(3-[2-(benzyloxy)phenyl]-5-(chloromethyl)isoxazole).

In one embodiment, the additional therapeutic agent is selected from acompound disclosed in Published Interanational Patent Application No.WO2014078842 or WO2012158885, or in United States Published ApplicationNo. US20140073667; all published international patent applications andpublished US patent application are hereby incorporated in theirentirety by reference.

In one embodiment, the additional therapeutic agent is selected from acompound disclosed in Published International Patent Application No:WO2012078909; WO2012154880; WO2012154888; WO2012154967; WO2013112651;WO2013112699; or WO2012078902; all published international patentapplications are hereby incorporated in their entirety by reference.

In one embodiment, the additional therapeutic agent is selected from acompound disclosed in US Patent No. 8,247,436 or 8,476,269; US PatentApplication No. 13/923,349; and Published International PatentApplication No: WO2011113894, WO2013038373, WO2013038378, WO2013038381,WO2013038386, or WO2013038390; all US patents, US patent applications,and published international patent applications are hereby incorporatedin their entirety by reference.

In one embodiment, the additional therapeutic agent is sleeted from acompound disclosed in WO2014210159 or WO2014152213; all publishedinternational patent applications are hereby incorporated in theirentirety by reference.

In one embodiment, the additional therapeutic agent is selected from acompound disclosed in Published International Patent Application No.:WO2014210159 or WO2014152213; all published international patentapplications are hereby incorporated in their entirety by reference.

In one embodiment, the additional therapeutic agent is selected from acompound disclosed in Published International Patent Application No.:WO2015003083, WO2015007517, WO2015007519, or WO2015007516; all publishedinternational patent applications are hereby incorporated in theirentirety by reference.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) acompound disclosed in U.S. Pat. Nos. 8,247,436 or 8,476,269; US PatentApplication No. 13/923,349; and Published International PatentApplication No: WO2011113894, WO2013038373, WO2013038378, WO2013038381,WO2013038386, or WO2013038390; all US patents, US patent applications,and published international patent applications are hereby incorporatedin their entirety by reference.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c) a compound disclosed in U.S. Pat. No. 8,247,436 or 8,476,269;U.S. patent application No. 13/923,349; and Published InternationalPatent Application No: WO2011113894, WO2013038373, WO2013038378,WO2013038381, WO2013038386, or WO2013038390; all US patents, US patentapplications, and published international patent applications are herebyincorporated in their entirety by reference.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound disclosed in U.S. Pat.Nos. 8,247,436 or 8,476,269; U.S. patent application Ser. No.13/923,349; and Published International Patent Application No:WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, orWO2013038390; all US patents, US patent applications, and publishedinternational patent applications are hereby incorporated in theirentirety by reference.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b) a compounddisclosed in U.S. Pat. No. 8,247,436 or 8,476,269; U.S. patentapplication Ser. No. 13/923,349; and. Published International PatentApplication No: WO2011113894, WO2013038373, WO2013038378, WO2013038381,WO2013038386, or WO2013038390; all US patents, US patent applications,and published international patent applications are hereby incorporatedin their entirety by reference; and c)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; c) acompound disclosed in U.S. Pat. Nos. 8,247,436 or 8,476,269; U.S. patentapplication Ser. No. 13/923,349; and Published International PatentApplication No: WO2011113894, WO2013038373, WO2013038378, WO2013038381,WO2013038386, or WO2013038390; all. US patents, US patent applications,and published international patent applications are hereby incorporatedin their entirety by reference; and d)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;c) a compound disclosed in U.S. Pat. No. 8,247,436 or 8,476,269; U.S.patent application Ser. No. 13/923,349; and Published InternationalPatent Application No: WO2011113894, WO2013038373, WO2013038378,WO2013038381, WO2013038386, or WO2013038390; all US patents, US patentapplications, and published international patent applications are herebyincorporated in their entirety by reference; and d)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; c) a compound disclosed in U.S. Pat. No.8,247,436 or 8,476,269; U.S. patent application Ser.No. 13/923,349; andPublished International Patent Application No: WO2011113894,WO2013038373, WO2013038378, WO2013038381, WO2013038386, or WO2013038390;all US patents, US patent applications, and published internationalpatent applications are hereby incorporated in their entirety byreference; and d)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) acompound disclosed in Published International Patent Application No:WO2012078909; WO2012154880; WO2012154888; WO2012154967; WO2013112651;WO2013112699; or WO2012078902; all published international patentapplications are hereby incorporated in their entirety by reference.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c) a compound disclosed in Published International PatentApplication No: WO2012078909; WO2012154880; WO2012154888; WO2012154967;WO2013112651; WO2013112699; or WO2012078902; all published internationalpatent applications are hereby incorporated in their entirety byreference.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula. I; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound disclosed in PublishedInternational Patent Application No: WO2012078909; WO2012154880;WO2012154888; WO2012154967; WO2013112651; WO2013112699; or WO2012078902;all published international patent applications are hereby incorporatedin their entirety by reference.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; c) acompound disclosed in Published International Patent Application No:WO2012078909; WO2012154880; WO2012154888; WO2012154967; WO2013112651;WO2013112699; or WO2012078902; all published international patentapplications are hereby incorporated in their entirety by reference; andd)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b) (R)1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;c) a compound disclosed in Published International Patent ApplicationNo: WO2012078909; WO2012154880; WO2012154888; WO2012154967;WO2013112651; WO2013112699; or WO2012078902; all published internationalpatent applications are hereby incorporated in their entirety byreference; and d)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; c) a compound disclosed in PublishedInternational Patent Application No: WO2012078909; WO2012154880;WO2012154888; WO2012154967; WO2013112651; WO2013112699; or WO2012078902;all published international patent applications are hereby incorporatedin their entirety by reference; and d)N-(5-hydroxy-2,4-ditert-butyl-pbenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the additional therapeutic agent is a compounddisclosed in Published International Patent Application No. WO2014099673hereby incorporated in its entirety by reference, including but notlimited to the following compounds:

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) acompound selected from P-1 to P-16 disclosed above.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) acompound selected from P-1 to P-16 disclosed above.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c) a compound selected from P-1 to P-16 disclosed above.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c) a compound selected from P-1 to P-16 disclosed above.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound selected from P-1 toP-16 disclosed above.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and c) a compound selected from P-1 toP-16 disclosed above.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; c) acompound selected from P-1 to P-16 disclosed above; and d)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of Table 1; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; c) acompound selected from P-1 to P-16 disclosed above; and d)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;c) a compound selected from P-1 to P-16 disclosed above; and d)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the invention features a pharmaceuticalcomposition comprising a) a compound of formula I; b)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; c) a compound selected from P-1 to P-16disclosed above; and d)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound of formula I; and b) a compound disclosed inU.S. Pat. No. 8,865,902. In some embodiments, the invention features apharmaceutical composition comprising a) a compound of Table 1; and b) acompound disclosed in U.S. Pat. No. 8,865,902. In another embodiment,the compound disclosed in U.S. Pat. No. 8,865,902 has the followingstructure:

wherein the compound disclosed in U.S. Pat. No. 8,865,902 is any one ofthe compounds of the following table:

X¹ X² X³ X⁴ X⁵ X⁶ X⁷ Y¹ Y² Y³ Y⁴ Y⁵ Y⁶ D D D D D D D CD₃ CD₃ CD₃ CD₃ CD₃CD₃ H H H H D H H CD₃ CD₃ CD₃ CD₃ CD₃ CD₃ H H H H D H H CD₃ CD₃ CD₃ CH₃CH₃ CH₃ H H H H D H H CH₃ CH₃ CH₃ CD₃ CD₃ CD₃ H H H H D H H CH₃ CH₃ CH₃CH₃ CH₃ CH₃ H H H H H H H CD₃ CD₃ CD₃ CD₃ CD₃ CD₃ H H H H H H H CD₃ CD₃CD₃ CH₃ CH₃ CH₃ H H H H H H H CH₃ CH₃ CH₃ CD₃ CD₃ CD₃

In another embodiment, the compound disclosed in U.S. Pat. No. 8,865,902is any one of the compounds of the following table:

X¹ X² X³ X⁴ X⁵ X⁶ X⁷ Y¹ Y² Y³ Y⁴ Y⁵ Y⁶ H H H H H D D CD₃ CD₃ CD₃ CD₃ CD₃CD₃ H H H H D D D CD₃ CD₃ CD₃ CD₃ CD₃ CD₃ H H H H D D D CD₃ CD₃ CD₃ CH₃CH₃ CH₃ H H H H D D D CH₃ CH₃ CH₃ CD₃ CD₃ CD₃ H H H H D D D CH₃ CH₃ CH₃CH₃ CH₃ CH₃ H H H H H D D CD₃ CD₃ CD₃ CH₃ CH₃ CH₃ H H H H H D D CH₃ CH₃CH₃ CD₃ CD₃ CD₃ D D D D D D D CD₃ CD₃ CD₃ CH₃ CH₃ CH₃ D D D D D D D CH₃CH₃ CH₃ CD₃ CD₃ CD₃ D D D D D H H CD₃ CD₃ CD₃ CH₃ CH₃ CH₃ D D D D D H HCH₃ CH₃ CH₃ CD₃ CD₃ CD₃ H H H H H H D CD₃ CD₃ CD₃ CD₃ CD₃ CD₃ H H H H HH D CD₃ CD₃ CD₃ CH₃ CH₃ CH₃ H H H H H H D CH₃ CH₃ CH₃ CD₃ CD₃ CD₃ H H HH H D H CD₃ CD₃ CD₃ CD₃ CD₃ CD₃ H H H H H D H CD₃ CD₃ CD₃ CH₃ CH₃ CH₃ HH H H H D H CH₃ CH₃ CH₃ CD₃ CD₃ CD₃

In another embodiment, the compound disclosed in U.S. Pat. No. 8,865,902is any one of the compounds of the following table:

X¹ X² X³ X⁴ X⁵ X⁶ X⁷ Y¹ Y² Y³ Y⁴ Y⁵ Y⁶ D D D D D H H CD₃ CD₃ CD₃ CD₃ CD₃CD₃ D D D D D D D CH₃ CH₃ CH₃ CH₃ CH₃ CH₃ D D D D D H H CH₃ CH₃ CH₃ CH₃CH₃ CH₃ D D D D H D D CD₃ CD₃ CD₃ CD₃ CD₃ CD₃ D D D D H H H CD₃ CD₃ CD₃CD₃ CD₃ CD₃ D D D D H D D CH₃ CH₃ CH₃ CH₃ CH₃ CH₃ D D D D H H H CH₃ CH₃CH₃ CH₃ CH₃ CH₃ H H H H H D D CH₃ CH₃ CH₃ CH₃ CH₃ CH₃

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound of formula I; and b) the compound:

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound of Table 1; and b) the compound:

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound of formula I; b)3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) thecompound:

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound of Table 1; b)3-(6-(1-(2,2-difluorobenzo[d][1,3[dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) thecompound:

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound selected from Compound 233, Compound 238,Compound 318, Compound 228, Compound 196, Compound 337, Compound 368,Compound 182, Compound 1356, Compound 172, Compound 639, Compound 300,Compound 1660, Compound 234, Compound 1975, Compound 262, Compound 2191,Compound 207, Compound 320, Compound 353, Compound 171, Compound 114,Compound 321, Compound 15, Compound 265, Compound 164, Compound 214,Compound 345, Compound 8, Compound 110, Compound 281, Compound 351,Compound 197, Compound 136, Compound 307, Compound 279, Compound 72,Compound 125, Compound 45, Compound 299, Compound 365, or Compound 361;b) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) thecompound:

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound of formula I; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c) the compound:

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound of Table 1; b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c) the compound:

In some embodiments, the invention features a pharmaceutical compositioncomprising a) a compound selected from Compound 233, Compound 238,Compound 318, Compound 228, Compound 196, Compound 337, Compound 368,Compound 182, Compound 1356, Compound 172, Compound 639, Compound 300,Compound 1660, Compound 234, Compound 1975, Compound 262, Compound 2191,Compound 207, Compound 320, Compound 353, Compound 171, Compound 114,Compound 321, Compound 15, Compound 265, Compound 164, Compound 214,Compound 345, Compound 8, Compound 110, Compound 281, Compound 351,Compound 197, Compound 136, Compound 307, Compound 279, Compound 72,Compound 125, Compound 45, Compound 299, Compound 365, or Compound 361;b)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and c) the compound:

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In one embodiment, any of the below therapeutic agents can be used alonewith a compound of formula I or Id, or in combination with any of theabove described pharmaceutical compositions, or as a component in any ofthe above described pharmaceutical compositions.

In one embodiment, the additional therapeutic agent is selected from amucolytic agent, bronchodialator, an antibiotic, an anti-infectiveagent, a CFTR modulator, or an anti-inflammatory agent.

In one embodiment, any of the below therapeutic agents, whichpredominantly treat the symptoms a CFTR mediated disease, such as cysticfibrosis, rather than its underlying cause, can be used alone with acompound of formula I, or in combination with any of the above describedpharmaceutical compositions, or as a component in any of the abovedescribed pharmaceutical compositions.

In one embodiment, the additional therapeutic agent is an antibiotic.Exemplary antibiotics useful herein include tobramycin, includingtobramycin inhaled powder (TIP), azithromycin, cayston, aztreonam,including the aerosolized form of aztreonam, amikacin, includingliposomal formulations thereof, ciprofloxacin, including formulationsthereof suitable for administration by inhalation, levoflaxacin,including aerosolized formulations thereof, and combinations of twoantibiotics, e.g., fosfomycin and tobramycin.

In another embodiment, the additional therapeutic agent is a mucolyte.Exemplary mucolytes useful herein includes Pulmozyme®.

In another embodiment, the additional therapeutic agent is abronchodialator. Exemplary bronchodialtors include albuterol,metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabulinesulfate.

In another embodiment, the additional therapeutic agent is effective inrestoring lung airway surface liquid. Such agents improve the movementof salt in and out of cells, allowing mucus in the lung airway to bemore hydrated and, therefore, cleared more easily. Exemplary such agentsinclude hypertonic saline, denufosol tetrasodium([[(3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl][[[(2R,3S,4R,5R)-5-(2,4-dioxopyrirnidin-1-yl)-3,4-dihydroxyoxolan-2-yl[methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]hydrogen phosphate), or bronchitol (inhaled formulation of mannitol).

In another embodiment, the additional therapeutic agent is ananti-inflammatory agent, i.e., an agent that can reduce the inflammationin the lungs. Exemplary such agents useful herein include ibuprofen,docosahexanoic acid (DHA), sildenafil, inhaled glutathione,pioglitazone, hydroxychloroquine, or simavastatin.

In another embodiment, the additional therapeutic agent is a compoundthat augments or induces CFTR activity other than a compound of formulaI. Exemplary such agents include ataluren (“PTC124®”;345-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), sinapultide,lancovutide, depelestat (a human recombinant neutrophil elastaseinhibitor), and cobiprostone (7-{(2R, 4aR, 5R,7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxonctahydrocyclopenta[b]pyran-5-yl}heptanoicacid).

In another embodiment, the additional therapeutic agent is a nutritionalagent. Exemplary nutritional agents include pancrelipase (pancreatingenzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, orCreon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathioneinhalation. In one embodiment, the additional nutritional agent ispancrelipase.

In another embodiment, the additional therapeutic agent is a compoundselected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate,miglustat, felodipine, nimodipine, Philoxin B, geniestein, Apigenin,cAMP/cGMP augmenters or inducers such as rolipram, sildenafil,milrinone, tadalafil, amrinone, isoproterenol, albuterol, and almeterol,deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors, proteosomeinhibitors such as epoxomicin, lactacystin, etc.

In other embodiments, the additional therapeutic agent is a compounddisclosed in WO 2004028480, WO 2004110352, WO 2005094374, WO 2005120497,or WO 2006101740, incorporated herein in their entirety by reference. Inanother embodiment, the additional agent is a benzo[c]quinoliziniumderivative that exhibits CFTR inducing or augmenting activity or abenzopyran derivative that exhibits CFTR inducing or augmentingactivity. In another embodiment, the additional agent is a compounddisclosed in U.S. Pat. No. 7,202,262, U.S. Pat. No. 6,992,096,US20060148864, US20060148863, US20060035943, US20050164973,WO2006110483, WO2006044456, WO2006044682, WO2006044505, WO2006044503,WO2006044502, or WO2004091502, incorporated herein in their entirety byreference. In another embodiment, the additional agent is a compounddisclosed in WO2004080972, WO2004111014, WO2005035514, WO2005049018,WO2006099256, WO2006127588, or WO2007044560, incorporated herein intheir entirety by reference.

In another embodiment, the additional therapeutic agent is a compounddisclosed in WO2014180562 or US20140274933, incorporated herein in theirentirety by reference.

In another embodiment, the additional therapeutic agent is selected fromthe categories ENaC inhibitors, betamimetics, anticholinergics,corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors,dopamine agonists, Ill-antihistamines, PAF-antagonists, MAP-kinaseinhibitors, MPR4-Inhibitors, iNOS-lnhibitors, or SYK-Inhibitors, ordouble or triple combinations thereof.

In another embodiment, the additional therapeutic agent is an ENaCinhibitor selected from3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxc acid(3,3,3-trifluoro-2-hydroxy -2-methyl-propyl)-amide;

5-amino-6′-methyl-3-trifluoromethyl-[2,3]bipyridinyl-6-carboxc acid(3,3,3-trifluoro-2-hydroxy -2-methyl-propyl)-amide;

3-amino-6-cyclopropyl-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyppropyl)-5-(trifluoromethyl)picolinamide;

3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxc acid((S)-3,3,3-trifluoro-2-hydroxy -2-methyl-propyl)-amide;

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxcacid((S-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxc acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid ((R)-3,3,3-trifluoro -2-hydroxy-2-methyl-propyl)-amide;

3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid(2-hydroxy-2-methyl-propyl)-amide;

3-amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

3-amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

(S)-3-amino-6-ethoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

3-amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;

3-amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide, orpharmaceutically acceptable salts thereof.

In another embodiment, the additional agent is a compound disclosed inU.S. Pat. No. 8,247,436 and International PCT Publication WO 2011113894,incorporated herein in their entirety by reference.

In another embodiment, the additional therapeutic agent is abetarnimetic selected from. Albuterole, Arformoterole, Bambuterole,Bitolterole, Broxaterole, Carbuterole, Clenbuterole, Fenoterole,Formoterole, Hexoprenaline, Ibuterole, Isoetharine, Isoprenaline,Levosalbutamole, Mabuterole, Meluadrine, Metaproterenole, Milveterol,Orciprenaline, Pirbuterole, Procaterole, Reproterole, Rimiterole,Ritodrine, Salmefamole, Salmeterole, Soterenole, Sulphonterole,Terbutaline, Tiaramide, Tolubuterole, Zinterole, Nolomirole, and

1-(2-chloro-4-hydroxyphenyl)-t-butylaminoethanole;

(−)-2-[7(S)-[2(R)-Hydroxy-2-(4-hydroxyphenyl)-ethylamino]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetamidehydrochloride monohydrate;

3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-oxy}-butyl)-benzyl-sulfonamide;

5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one;

4-Hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl]ethyl]-amino}ethy-1]-2(3H)-benzothiazolone;

1-(2-Fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol;

1-[3-(4-Methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol;

1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoplienyl)-2-methyl-2-propylan⁻unolethanol;

1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol;

1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol;

1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-(4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol;

5-Hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one;

1-(4-Amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol;

6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;

6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acidethylester)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;

6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo [1,4]oxazin-3-one;

8-{2-[1,1-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-e-thyl}-4H-benzo[1,4]oxazin-3-one;

6-Hydroxy-8-(1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;

8-{2-[2-(4-Ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl-phenoxy)-butyric acid;

8-{2-[2-(3,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

1-(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol;

N-[2-Hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide;

8-Hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one;

8-Hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one;

5-[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one;

[3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]hexyl-oxy-butyl)-5-methyl-phenyl]-urea;

4-(2-{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy}-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenole;

3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-oxy}-butyl)-benzenesulfonamide;

3-(3-{7-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hepty-loxy}-propyl)-benzenesulfonamide;

4-(2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenole;

N-Adamantan-2-yl-2-(3-2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;

(R,S)-4-(2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;

(R,S)-4-(2-[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;

(R,S)-4-(2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxy-methyl)phenol;

(R,S)-4-(2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;

(R,S)-5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one;

(R,S)-[2-({6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;

4-(1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino)-1-hydroxyethyl)-2-(hydroxymethyl)phenol;

(R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-[4,4,515-tetrafluoro-6-(3-phenylpropoxy)-hexyl]amino]ethyl)phenol;

(R,S)-[5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino-1-hydroxy-ethyl-)-2-hydroxy-phenyl]formamide;

(R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;

(R,S)—N-[3-(1,1-Difluoro-2-[6-(2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]urea;

3-[3-(1,1-difluoro-2-[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione;

(R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexy}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;

5-((1R)-2-[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one;

4-((1R)-2-[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;

(R,S)-4-(2-[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl-)-2-(hydroxymethyl)phenol;

(R,S)-(2-{[6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;

(R,S)-4-(2-[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxy-methyl)phenol;

3-[2-(3-Chloro-phenyl)-ethoxyl-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide;

N-(2-Diethylamino-ethyl)-N-2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide;

7-[2-(2-3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one;or

7-[(1R)-2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxyethyl]-4-hydroxy-3H-benzothiazol-2-one;optionally in racemic form, as enantiomers, diastereomeres or aspharmaceutically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate.

In one embodiment, the additional therapeutic agent is ananticholinergic selected from Tiotropium salts, preferably the bromidesalt, Oxitropium salts, preferably the bromide salt, Flutropium salts,preferably the bromide salt, Ipratropium salts, preferably the bromidesalt, Aclidinium salts, preferably the bromide salt, Glycopyrroniumsalts, preferably the bromide salt, Trospium salts, preferably thechloride salt, Tolterodin. From the above mentioned salts thepharmaceutically active part is the cation, possible anions arechloride, bromide, iodide, sulfate, phosphate, methansulfonate, nitrate,maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate,benzoate or p-toluenesulfonate. Further examples of preferredanticholinergics are selected from among

2,2-Diphenylpropionic acid tropenole ester-methobromide;

2,2-Diphenylpropionic acid scopine ester-methobromide;

2-Fluor-2,2-Diphenylacetic acid scopine ester-methobromide;

2-Fluor-2,2-Diphenylacetic acid tropenole ester-methobromide;

3,3′,4,4′-Tetrafluorbenzil acid tropenole ester-methobromide;

3,3′,4,4′-Tetrafluorbenzil acid scopine ester-methobromide;

4,4′-Difluorbenzil acid tropenole ester-methobromide;

4,4′-Difluorbenzil acid scopine ester-methobromide;

3,3′-Difluorbenzil acid tropenole ester-methobromide;

3,3′-Difluorbenzil acid scopine ester-methobromide;

9-Hydroxy-fluorene-9-carbon acid tropenole ester-methobromide;

9-Fluor-fluorene-9-carbon acid tropenole ester-methobromide;

9-Hydroxy-fluorene-9-carbon acid scopine ester-methobromide;

9-Fluor-fluorene-9-carbon acid scopine ester methobromide;

9-Methyl-fluorene-9-carbon acid tropenole estermethobromide;

9-Methyl-fluorene-9-carbon acid scopine estermethobromide;

Benzil acid cyclopropyl tropine ester-methobromide;

2,2-Diphenylpropionic acid cyclopropyl tropine ester-methobromide;

9-Hydroxy-xanthene-9-carbon acid cyclopropyl tropine ester-methobromide;

9-Methyl-fluorene-9-carbon acid cyclopropyl tropine ester-methobromide;

9-Methyl-xanthene-9-carbon acid cyclopropyl tropine ester-methobromide;

9-Hydroxy-fluorene-9-carbon acid cyclopropyl tropine ester-methobromide;

4,4″-Difluorbenzil acid methylester cyclopropyl tropineester-methobromide;

9-Hydroxy-xanthene-9-carbon acid tropenole ester-methobromide;

9-Hydroxy-xanthene-9-carbon acid scopine ester methobromide;

9-Methyl-xanthene-9-carbon acid tropenole ester-methobromide;

9-Methyl-xanthene-9-carbon acid scopine estermethobromide;

9-Ethyl-xanthene-9-carbon acid tropenole ester methobromide;

9-Difluormethyl-xanthene-9-carbon acid tropenole ester-methobromide; or

9-Hydroxymethyl-xanthene-9-carbon acid scopine ester methobromide.

In one embodiment, the additional therapeutic agent is a corticosteroidselected from Beclomethasone, Betamethasone, Budesonide, Butixocorte,Ciclesonide, Deflazacorte, Dexamethasone, Etiprednole, Flunisolide,Fluticasone, Loteprednole, Mometasone, Prednisolone, Prednisone,Rofleponide, Triamcinolone, Tipredane,

{20R-16alpha,17alpha-[butylidenebis(oxy)]-6alpha,9alpha-difluoro-11beta-hydroxy-17beta-(methylthio)androsta-4-en-3-one};

9-fluoro-11beta,17,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione21-cyclohexanecarboxylate 17-cyclopropanecarboxylate;

16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one;

Flunisolide-21-[4″-(nitrooxymethyl)benzoate];

6,9-Difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-dien-17-carbothionacid (S)-fluoromethylester;

6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-17-carbothionacid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester; or

6alpha,9alpha-difluoro-11beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylicacid cyanomethyl ester; optionally in racemic form, as enantiomers,diastereomeres or as pharmaceutically acceptable salts, solvates orhydrates. Examples for preferred salts and derivatives are alkali salts,i.e. sodium or potassium salts, sulfobenzoates, phosphates,isonicotinates, acetates, dichloroacetates, propionates,dihydrogenphosphates, palmitates, pivalates or furoates.

In one embodiment, the additional therapeutic agent is a PDE4-inhibitorselected from Enprofylline, Theophylline, Roflumilaste, Ariflo(Cilomilaste), Tofimilaste, Pumafentrine, Lirimilaste, Apremilaste,Arofylline, Atizorame, Oglemilasturn, Tetomilaste;

5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamidel-8-methoxy-quinoline;

5-[N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-quinoline;

N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]glyoxylacid amide);

9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purine-6-amine;

4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine;

N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk-][1,4]benzodiazepin-3-yl]-4-Pyridinecarboxamide;

4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-pyridinone;

2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-Phthalazinone;

(3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine;

beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide;

9-ethyl-2-methoxy-7-methyl-5-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(-5H)-one;

5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl](3S,5S)-2-piperidinone;

4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinypethyl]-alpha,alpha-bis(trifluoromethyl)-Benzenemethanol;

N-(3,5-Dichloro-1-oxo-pyridine-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxy-benzamide;

(−)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methyl-benzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide;

(R)-(+)-1-(4-Bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;

3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methyl-isothioureido]-benzyl)-2-pyrrolidone;

cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carbonacid];

2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexan-1-one;

cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];

(R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyppyrrolidine-2-yliden]acetate;

(S)-(−)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyppyrrolidine-2-yliden]acetate;

9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;or

9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine;optionally in racemic form, as enantiomers, diastereomeres or aspharmaceutically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate.

In one embodiment, the additional therapeutic agent is a LTD4-antagonistselected from Montelukast, Pranlukast, Zafirlukast, Masikulast, L-733321(see compound 2ab of D. Guay et al, Bioorg. Med. Chem. Lett. 8 (1998)453-458);

(E)-842-[4-[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazole-5-yl)-4H-1-benzopyran-4-one;

4-[6-Acetyl-343-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxyl-2-propyl-phenoxy]-butyricacid;

1-a(R)-(3-(2-(6,7-Difluoro-2-quinolinypethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenypthio)methylcyclopropane-aceticacid;

1-(((1(R)-3(3-(2-(2,3-Dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid; or

[2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyliphenyl]aceticacid; optionally in racemic form, as enantiomers, diastereomeres or aspharmaceutically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate. Further examples for optionally preferredsalts and derivatives are alkali salts, i.e. sodium or potassium salts,sulfobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogenphosphates, palmitates, pivalates or furoates.

In one embodiment, the additional therapeutic agent is an EGFR-inhibitorselected from Cetuximab, Trastuzumab, Panitumumab Gefitinib, Canertinib,Erlotinib, Mab ICR-62;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino1-7-cyclopropylmethoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline;

4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl-]amino}-7-cyclopentyloxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino1-7-cyclopropylmethoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino)-7-cyclopropylmethoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline;

4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline;

4-[(R)-(1-Phenyl-ethyl)amino]-6-{4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-butene-1-yl)amino)-7-cyclopropylmethoxy-quinazoline;

4-[(R)-(1-Phenyl-ethypaminol-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline;

4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-ylamino)-7-cyclopentyloxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-butene-1-yl]amino)-7-cyclopentyloxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino)-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino)-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-7-[3-(morpholine-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline;

4-[(R)-(1-Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine;

3-Cyano-4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-ethoxy-quinoline;

4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-[(2-methansulfonyl-ethyl)amino]methyl-furan-2-yl)quinazoline;

4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline;

4-[(3-Chlor-4-fluorophenyflamino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-butene-1-yl)amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(trans-4-annno-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(trans-4-methansuffonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(piperidine-3-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidine-4-yloxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)annno]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline;

4-[(3-Chlor-4-fluorophenypanfino]-64S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino[-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonylamino]-cyclonexane-1-yloxy-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{trans-4-[(morpholine-4-yl)sulfonylamino]-cyclohexane-1-yloxy-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetyl-amino-ethoxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino[-6-(tetrahydropyran-4-yloxy)-7-(2-methane-sulfonylamino-ethoxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[(piperidine-1-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-aminocarbonylmethyl-piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino]-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(cis-4-N-[(morpholine-4-yl)sulfonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-ethoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino[-6-[1-(2-methoxy-acetyl)-piperidine-4-yl-oxy]-7-(2-methoxy-ethoxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(cis-4-acetylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(cis-4-N-[(piperidine-1-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazine-1-yl)-carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{cis-4-[(morpholine-4-yl)carbonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[2-(2-oxopyrrolidine-1-yl)ethyl]-piperidine-4-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-isopropyloxycarbonyl-piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(cis-4-methylamino-cyclohexane-1-yloxy)-7-methoxy-chinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-(piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4-yloxy]-7-methoxy-quinazoline;

4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[cis-2,6-dimethyl-morpholine-4-yl)-carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[(2-methyl-morpholine-4-yl)carbony-1]-piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]-hept-5-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)-carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-ethyl-piperidine-4-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-[(2-methoxyethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidine-4-yloxy-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(trans-4-methylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(trans-4-dimethylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(trans-4-{N-[(morpholine-4-yl)carbony-1]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline;

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-methoxy-quinazoline;or

4-[(3-Chlor-4-fluorophenyl)amino]-6-(1-cyano-piperidine-4-yloxy)-7-methoxy-quinazoline;optionally in racemic form, as enantiomers, diastereomeres or aspharmaceutically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate.

In another embodiment, the additional therapeutic agent is a dopamineantagonist selected from Bromocriptine, Cabergoline,Alpha-Dihydroergocryptine, Lisuride, Pergolide, Prarnipexole, Roxindole,Ropinirole, Talipexole, Terguride and Viozane, optionally in racemicform, as enantiomers, diastereomeres or as pharmaceutically acceptablesalts, solvates or hydrates. Preferred are salts selected from the groupconsisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate,hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

In another embodiment, the additional therapeutic agent is anantiallergic agent selected from Epinastine, Cetirizine, Azelastine,Fexofenadine, Levocabastine, Loratadine, Mizolastine, Ketotifene,Emedastine, Dimetindene, Clemastine, Bamipine, Cexchlorpheniramine,Pheniramine, Doxylamine, Chlorphenoxamine, Dimenhydrinate,Diphenhydramine, Promethazine, Ebastine, Olopatadine, Desloratidine andMeclozine, optionally in racemic form, as enantiomers, diastereomeres oras pharmaceutically acceptable salts, solvates or hydrates. Preferredare salts selected from the group consisting of hydrochloride,hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

In one embodiment, the additional therapeutic agent is an. MAP kinaseinhibitor selected from Benta.mapimod, Doramapimod, 5-Carbamoylindole,6-Raminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridinecarboxamide,alphat2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazoleacetonitrile,9,12-Epoxy-1H-diindolo[1,2,3-fg:3″,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazo-cine-10-Carboxylicacid, or4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1H-pyrazole-4-yl]-pyrimidine,optionally in racemic form, as enantiomers, diastereomeres or aspharmaceutically acceptable salts, solvates or hydrates. Preferred aresalts selected from the group consisting of hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate.

In one embodiment, the additional therapeutic agent is an MRP4-Inhibitorselected from N-Acetyl-dinitrophenyl-Cysteine, cGMP, Cholate,Diclofenac, Dehydroepiandrosterone 3-glucuronide, Dehydroepiandrosterone3-sulphate, Dilazep, Dinitrophenyl-S-glutathione, Estradiol17-beta-glucuronide, Estradiol 3,17-disulphate, Estradiol 3-glucuronide,Estradiol 3-sulphate, Estrone 3-sulphate, Flurbiprofen, Folate,N5-formyl-tetrahydrofolate, Glycocholate, Glycolithocholic acidsulphate, Ibuprofen, Indomethacin, Indoprofen, Ketoprofen, Lithocholicacid sulphate, Methotrexate,(E)-3-[[[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid, alpha-Naphthyl-beta-D-glucuronide, Nitrobenzyl mercaptopurineriboside, Probenecid, Valspodar, Sildenafil, Sulfinpyrazone,Taurochenodeoxycholate, Taurocholate, Taurodeoxycholate,Taurolithocholate, Taurolithocholic acid sulphate, Topotecan,Trequinsin, Zaprinast or Dipyridamol, optionally in racemic form, asenantiomers, diastereomers or as pharmaceutically acceptable salts,solvates or hydrates. Preferred are salts selected from the groupconsisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate,hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

In one embodiment, the additional therapeutic is an iNOS-Inhibitorselected from S-(2-Aminoethyl)isothio-urea, Aminoguanidine,2-Aminomethylpyridine, 5,6-dihydro-6-methyl-4H-1,3-thiazine-2-amine(AMT), L-Canavanin, 2-Iminopiperidine, S-Isopropylisothiourea,S-Methylisothiourea, S-Ethylisothiourea, S-Methylthiocitrulline,S-Ethylthiocitrulline, L-NA (N^(ω)-Nitro-L-arginin), L-NAME(N^(ω)-Nitro-L-argininmethylester), L-NMMA (N^(ω)-Monomethyl-L-arginin),L-NIO (N^(ω)-Iminoethyl-L-ornithin), L-NIL (N^(ω)-iminoethyl-lysin),

(S)-6-Acetimidoylamino-2-amino-hexanoic acid (1H-tetrazole-5-yl)-amide;

N-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide;

(S)-4-(2-acetimidoylamino-ethylsulfanyl)-2-amino-buturic acid;

2-[2-(4-Methoxy-pyridine-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine;

2-((R)-3-amino-1-phenyl-propoxy)-4-chlor-5-fluorbenzonitrile;

2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-yl-butylsulfanyl)-6-trifluoromethyl-nicotinonitrile;

2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-yl-butylsulfanyl)-4-chlor-benzonitrile;

2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-yl-butylsulfanyl)-5-chlor-benzonitrile;

(2S,4R)-2-amino-4-(2-chlor-5-trifluoromethyl-phenylsulfanyl)-4-thiazole-5-yl-butane-1-ol;

2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-yl-butylsulfanyl)-5-chlor-nicotinonitrile;

4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulfanyl)-6-methoxy-nicotinonitrile;or substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine as for instance1S,5S,6R)-7-Chlor-5-methyl-2-aza-bicyclo[4.1.0]hept-2-ene-3-ylamin(4R,5R)-5-Ethyl-4-methyl-thiazolidine-2-ylideneamine,(1S,5S,6R)-7-Chlor-5-methyl-2-aza-bicyclo[4.1.0]hept-2-ene-3-ylamin,(4R,5R)-5-Ethyl-4-methyl-thiazolidine-2-ylideneamine,(4R,5R)-5-Ethyl-4-methyl-selenazolidine-2-ylideneamine,4-Aminotetrahydrobiopterine,(E)-3-(4-Chlor-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluormethyl-pyrimidine-4-yloxy)-piperidine-1-yl}-ethylcarbamoyl}-2-pyridine-2-yl-ethyl)-acrylamide,3-(2,4-Difluor-phenyl)-6-[2-(4-imidazole-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine,3-{[(Benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl)-4-(2-imidazole-1-yl-pyrimidine-4-yl)-piperazine-1-carbonacid methylester, or(R)-1-(2-imidazole-1-yl-6-methyl-pyrimidine-4-yl)-pyrrolidine-2-carbonacid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide, optionally in racemic form,as enantiomers, diastereomeres or as pharmaceutically acceptable salts,solvates or hydrates. Preferred are salts selected from the groupconsisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate,hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. Furtherexamples of preferred iNOS-Inhibitors which may be mentioned includeantisense-Oligonucleotide, especially those antisense-oligonucleotidebinding iNOS-coding nucleic acids, examples therefore are disclosed inWO 01/52902, incorporated herein by reference in its entirety.

In another embodiment, the additional therapeutic agent is aSYK-inhibitor selected from

2-[(2-aminoethyl]-amino]-4-[(3-bromophenyl)amino]-5-pyrimidinecarboxamide;

2-[[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidine-5-yl]amino]-3-pyridinecarboxamide;

6-[[5-fluoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one;

N-[3-bromo-7-(4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

7-(4-methoxyphenyl)-N-methyl-1,6-naphthyridine-5-amine;

N-[7-(4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(2-thienyl)-1,6-naphthyridine-5-yl-1,3-propanediamine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-ethanediamine;

N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(4-methoxyphenyl)-3-phenyl-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-(7-phenyl-1,6-naphthyridine-5-yl)-1,3-propanediamine;

N-[7-(3-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanedi amine;

N-[7-(3-chlorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[3-(trifluoromethoxy)phenyl]-1,6-naphthyridine-5yl]-1,3-propanediamine;

N-[7-(4-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(4-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediarnine;

N-[7-(4-chlorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(4′-methyl[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-1,3-propane-diamine;

N-[7-(4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propane-diamine;

N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(4-bromophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(4-methylphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-(methylthio)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-(1-methylethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

7-[4-(dimethylamino)phenyl]-N-methyl-1,6-naphthyridine-5-amine;

7-[4-(dimethylamino)phenyl]-N,N-dimethyl-1,6-naphthyridine-5-amine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,4-butanediamine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,5-pentanediamine;

3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-ylioxy]-1-propanole;

4-[5-(4-aminobutoxy)-1,6-naphthyridine-7-yl]-N,N-dimethyl-benzenamine;

4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-1-butanole;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-N-methyl-1,3-propanediamine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-N′-methyl-1,3-propanediarnine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-N,N-dimethyl-1,3-propanediamine;

1-amino-3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-2-propanole;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-2,2-dimethyl-1,3-propanediamine;

7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1,6-naphthyridine-5-amine;

N-[(2-aminophenyl)methyl]-7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-amine;

N-[7-[6-(dimethylamino)[1,1′-biphenyl]-3-yl]-1,6-naphthyridine-5-yl]-1,3-propanediarnine;

N-[7-[3-chloro-4-(diethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-(diethylamino)phenyl]-3-methyl-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(3′-fluoro[1,1′-biphenyl]-3-yl)-1,6-naphthyridine-5-yl]-1,2-ethanediamine;

N-[7-(4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,6-naphthyridine-1,3-propanediamine;

N,N′-bis(3-aminopropyl)-7-(4-methoxyphenyl)-2,5-diamine;

N-[7-(4-methoxyphenyl)-2-(phenylmethoxy)-1,6-naphthyridine-5-yl]-1,6-naphthyridine-1,3-propanediamine;

N5-(3-aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamine;

N-[7-(2-naphthalenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(T-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(3,4-dimethylphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

1-amino-3-[[7-(2-naphthalenyl)-1,6-naphthyridine-5-yl]amino]-2-propanole;

1-amino-3-[[7-(2′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]amino]-2-propanole;

1-amino-3-[[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]amino]-2-propanole;

1-amino-3-[[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridine-5-yl]amino]-2-propanole;

1-amino-3-[[7-(4-bromophenyl)-1,6-naphthyridine-5-yl]amino]-2-propanole;

N-[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-2,2-dimethyl-1,3-propanediamine;

1-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-2-propanole;

2-[[2-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-ethyl]thiol-ethanole;

7-[4-(dimethylamino)phenyl]-N-(3-methyl-5-isoxazolyl)-1,6-naphthyridine-5-amine;

7-[4-(dimethylamino)phenyl]-N-4-pyrimidinyl-1,6-naphthyridine-5-amine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl[-1,3-cyclohexanediamine;

N,N-dimethyl-4-[5-(1-piperazinyl)-1,6-naphthyridine-7-yl]-benzenamine;

4-[5-(2-methoxyethoxy)-1,6-naphthyridine-7-yl]-N,N-dimethyl-benzeneamine;

1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-4-piperidinole;

1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-3-pyrrolidinole;

7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-1,6-naphthyridine-5-amine;

7-[4-(dimethylamino)phenyl]-N-[3-(1H-imidazole-1-yl)propyl]-1,6-naphthyridine-5-amine;

1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-4-piperidinecarboxamide;

1-[3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]propyl]-2-pyrrolidinone;

N-[3′-[5-[(3-aminopropyl)amino]-1,6-naphthyridine-7-yl][1,1′-biphenyl]-3-yl]-acetamide;

N-[7-(4′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[4′-[5-[(3-aminopropyl)amino]-1,6-naphthyridine-7-yl][1,1′-biphenyl]-3-yl]-acetamide;

N-[7-[4-(1,3-benzodioxol-5-yl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-(2-thienyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-(3-pyridinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(1,3-benzodioxol-5-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(6-methoxy-2-naphthalenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1,6-naphthyridine-5-amine;

3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]methylamino]-propanenitrile;

7-[4-(dimethylamino)phenyl]-N-[1-(phenylmethyl)-4-piperidinyl]-1,6-naphthyridine-5-amine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-cyclohexanediamine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-cyclohexanediamine,(1R,2S)-rel-;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-benzenedimethanamine;

N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,4-butanediamine;

N-[7-[3′,5′-bis(trifluoromethyl)[1,1′-biphenyl]-4-yl]-1,6-naphthyr-idine-5-yl]-3-propanediamine;

N-[7-(3′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propane-diamine;

N-[7-(3′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]oxy]-1-butanole;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;

7-[4-(dimethylamino)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-1,6-naphthyridine-5-amine;

N-[7-[3-bromo-4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propan-ediamine;

N-[7-(1-methyl-1H-indole-5-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[3-(trifluoromethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-(trifluoromethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(3-bromo-4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;

N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;

N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;

N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;

N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexane-diamine;

4-[[7-4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]oxy]-cyclohexanole;

N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propane-diamine;

N,N-dimethyl-4-[5-(4-methyl-1-piperazinyl)-1,6-naphthyridine-7-yl]-benzenamine;

4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]oxy]-cyclohexanole;

N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,4-butanediamine;or

[3-[[5-[(3-aminopropyl)amino]-7-(4-methoxyphenyl)-1,6-naphthyridine-2-yl]-amino]propyl]-carbamicacid-1,1-dimethylethyl ester, optionally in racemic form, asenantiomers, diastereomers or as pharmaceutically acceptable salts,solvates or hydrates. Preferred are salts selected from the groupconsisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate,hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

In another embodiment, the additional therapeutic agent is an agent thatinhibits the interaction between CAL (also known as CFTR-associatedligand) and mutant CFTR proteins. In one embodiment, the agent thatinhibits interaction between CAL and mutant CFTR proteins is a peptideor peptidomimetic (e.g., 6 to 20 residues in length). In anotherembodiment, the agent that inhibits interaction between CAL and mutantCFTR proteins is a peptide or peptidomimetic disclosed in US PublishedPatent Application No. US2014/0100155 A1, incorporated herein byreference in its entirety.

In another embodiment, the above recited pharmaceutical compositionscontain a pharmaceutically acceptable prodrug of the compound of thepresent invention.

In one aspect, the pharmaceutical compositions of the invention can beadministered to a patient once daily or about every twenty four hours.Alternatively, the pharmaceutical compositions of the invention can beadministered to a patient twice daily. Alternatively, the pharmaceuticalcomposition of the invention can be administered about every twelvehours. These pharmaceutical compositions are administered as oralformulations containing about 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 200mg, 250 mg, 300 mg, or 400 mg of a compound of Formula I. In thisaspect, the pharmaceutical compositions further comprise a filler; adisintegrant; a surfactant; a binder; or a lubricant, or combinationsthereof.

It will also be appreciated that the pharmaceutical compositions of theinvention, including the pharmaceutical compositions comprisingcombinations described previously, can be employed in combinationtherapies; that is, the compositions can be administered concurrentlywith, prior to, or subsequent to, one or more other desired therapeuticagents or medical procedures.

These combinations are useful for treating the diseases described hereinincluding cystic fibrosis. These combinations are also useful in thekits described herein.

The amount of additional therapeutic agent present in or with thecompositions of this invention will be no more than the amount thatwould normally be administered in a composition comprising thattherapeutic agent as the only active agent. Preferably the amount ofadditional therapeutic agent in the presently disclosed compositionswill range from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent.

Therapeutic Uses of the Compounds of Formula I-Ij and PharmaceuticalCompositions Thereof

In one aspect, the invention also provides a method of treating,lessening the severity of, or symptomatically treating a disease in apatient, the method comprising administering an effective amount of thepharmaceutical composition of the invention to the patient, preferably amammal, wherein the disease is selected from cystic fibrosis, asthma,smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation,pancreatitis, pancreatic insufficiency, male infertility caused bycongenital bilateral absence of the vas deferens (CBAVD), mild pulmonarydisease, idiopathic pancreatitis, allergic bronchopulmonaryaspergillosis (ABPA), liver disease, hereditary emphysema, hereditaryhemochromatosis, coagulation-fibrinolysis deficiencies, such as proteinC deficiency and Type 1 hereditary angioedema, lipid processingdeficiencies (such as familial hypercholesterolemia, Type 1chylomicronemia, and abetalipoproteinemia), lysosomal storage diseases(such as I-cell disease/pseudo-Hurler), mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,polyendocrinopathy/hyperinsulinemia, Diabetes mellitus, Laron dwarfism,myeloperoxidase deficiency, primary hypoparathyroidism, melanoma,glycanosis CDG type 1, congenital hyperthyroidism, osteogenesisimperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetesinsipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie Toothsyndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases (suchas Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, progressive supranuclear palsy, and Pick's disease), severalpolyglutamine neurological disorders (such as Huntington's,spinocerebellar ataxia type 1, spinal and bulbar muscular atrophy,dentatorubral pallidoluysian atrophy, and myotonic dystrophy),spongiform encephalopathies (such as hereditary Creutzfeldt-Jakobdisease (due to prion protein processing defect)), Fabry disease,Gerstmann-Straussler-Scheinker syndrome, COPD, dry-eye disease, orSjogren's disease, osteoporosis, osteopenia, bone healing and bonegrowth (including bone repair, bone regeneration, reducing boneresorption and increasing bone deposition), Gorham's Syndrome, chloridechannelopathies such as myotonia congenita (Thomson and Becker forms),Bartter's syndrome type III, Dent's disease, epilepsy, lysosomal storagedisease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a termfor inherited disorders of the structure and/or function of cilia,including PCD with situs inversus (also known as Kartagener syndrome),PCD without situs inversus and ciliary aplasia.

In another embodiment, the method of treating, lessening the severityof, or symptomatically treating a disease in a patient of the inventioncomprises administering an effective amount of the pharmaceuticalcomposition of the invention, provided that in formula and the attendantdefinitions: i) when ring A is indole, n is not zero and rings B and Care aryl unsubstituted by CF₃ or halo; ii) when ring A is pyrazole, n isnot zero; iii) when ring A is pyridyl, ring B and ring C moieties aresubstituted at the 2- and 3-positions of the pyridyl ring,interchangeably; and iv) when ring A is imidazole, the ring B moiety issubstituted at the 2-position of the imidazole ring.

In one aspect, the invention also provides a method of treating,lessening the severity of, or symptomatically treating a disease in apatient comprising administering an effective amount of thepharmaceutical composition or tablet of the invention to the patient,preferably a mammal, wherein the disease is selected from generalizedepilepsy with ferbrile seizures plus (GEFS+), general epilepsy withferbile and aferbrile seizures, myotonia, paramyotonia congenital,potassium-aggravated myotonia, hyperkalemic periodic paralysis, LQTS,LQTS/Brugada syndrome, autosomal-dominant LQTS with deafness,autosomal-recessive LQTS, LQTS with dysmorphic features, congenital andacquired LQTS, Timothy syndrome, persistent hyperinsulinemichypolglycemia of infancy, dilated cardiomyopathy, autosomal-dominantLQTS, Dent disease, Osteopetrosis, Bartter syndrome type III, centralcore disease, malignant hyperthermia, and catecholaminergic polymorphictachycardia.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation N1303K, ΔI507, or R560T.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation G551D. In another embodiment, the patient is homozygousin G551D. In another embodiment, the patient is heterozygous in G551D.In another embodiment, the patient is heterozygous in G551D, wherein theother CFTR genetic mutation is any one of F508del, G542X, N1303K,W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T,R1162X, G85E, 3120+1G->A, A1507, 1898+1G->A, 3659delC, R347P, R560T,R334W, A455E, 2184delA, or 711+1G->T. In another embodiment, the patientis heterozygous in G551D, wherein the other CFTR genetic mutation isF508del. In another embodiment, the patient is heterozygous in G551D,wherein the other CFTR genetic mutation is R117H.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation F508del. In another embodiment, the patient ishomozygous in F508del. In another embodiment, the patient isheterozygous in F508del. In another embodiment, the patient isheterozygous in F508del, wherein the other CFTR genetic mutation is anyone of G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A,621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, A1507,1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or711+1G->T. In another embodiment, the patient is heterozygous inF508del, wherein the other CFTR genetic mutation is G551D. In anotherembodiment, the patient is heterozygous in F508del, wherein the otherCFTR genetic mutation is R117H.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P,G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H,R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W,F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A,1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A,1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A,4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G,711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A,1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G,IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P,G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In oneembodiment of this aspect, the invention provides a method of treatingCFTR comprising administering Compound 1 to a patient possessing a humanCFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D,S549N, S549R and S1251N. In one aspect, the present invention isdirected to a method of treating, lessening the severity of, orsymptomatically treating cystic fibrosis in a patient comprisingadministering an effective amount of the pharmaceutical composition ortablet of the invention to the patient, preferably a mammal, wherein thepatient possesses the CFTR genetic mutation is selected from E193K,F1052V and G1069R. In some embodiments of this aspect, the methodproduces a greater than 10-fold increase in chloride transport relativeto baseline chloride transport.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from R117C, D110H, R347H, R352Q, E56K,P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270Nand D1152H. In one embodiment of this aspect, the method produces anincrease in chloride transport which is greater or equal to 10% abovethe baseline chloride transport.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A,1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A,1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A,4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G,711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A,1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G,IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G. In one aspect, thepresent invention is directed to a method of treating, lessening theseverity of, or symptomatically treating cystic fibrosis in a patientcomprising administering an effective amount of the pharmaceuticalcomposition or tablet of the invention to the patient, preferably amammal, wherein the patient possesses the CFTR genetic mutation isselected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and3849+10kbC->T. In one aspect, the present invention is directed to amethod of treating, lessening the severity of, or symptomaticallytreating cystic fibrosis in a patient comprising administering aneffective amount of the pharmaceutical composition or tablet of theinvention to the patient, preferably a mammal, wherein the patientpossesses the CFTR genetic mutation is selected from 2789+5G->A and3272-26A->G.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P,G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H,R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W,F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A,1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A,1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A,4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G,711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A,1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G,IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTRmutation selected from F508del, R117H, and G551D.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P,G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and a human CFTRmutation selected from F508del, R117H, and G551D. In one aspect, thepresent invention is directed to a method of treating, lessening theseverity of, or symptomatically treating cystic fibrosis in a patientcomprising administering an effective amount of the pharmaceuticalcomposition or tablet of the invention to the patient, preferably amammal, wherein the patient possesses the CFTR genetic mutation isselected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549Rand S1251N, and a human CFTR mutation selected from F508del, R117H, andG551D. In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from E193K, F1052V and G1069R, and a humanCFTR mutation selected from F508del, R117H, and G551D. In someembodiments of this aspect, the method produces a greater than 10-foldincrease in chloride transport relative to baseline chloride transport.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from R117C, D110H, R347H, R352Q, E56K,P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270Nand D1152H, and a human CFTR mutation selected from F508del, R117H, andG551D. In one embodiment of this aspect, the method produces an increasein chloride transport which is greater or equal to 10% above thebaseline chloride transport.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A,1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A,1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A,4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G,711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A,1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G,IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTRmutation selected from F508del, R117H, and G551D. In one aspect, thepresent invention is directed to a method of treating, lessening theseverity of, or symptomatically treating cystic fibrosis in a patientcomprising administering an effective amount of the pharmaceuticalcomposition or tablet of the invention to the patient, preferably amammal, wherein the patient possesses the CFTR genetic mutation isselected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and3849+10kbC->T, and a human CFTR mutation selected from F508del, R117H,and G551D. In one aspect, the present invention is directed to a methodof treating, lessening the severity of, or symptomatically treatingcystic fibrosis in a patient comprising administering an effectiveamount of the pharmaceutical composition or tablet of the invention tothe patient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from 2789₊5G->A and 3272-26A->G, and ahuman CFTR mutation selected from F508del, R117H.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P,G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H,R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W,F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A,1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A,1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A,4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G,711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A,1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G,IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTRmutation selected from F508del, R117H, and G551D.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P,G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In one aspect,the present invention is directed to a method of treating, lessening theseverity of, or symptomatically treating cystic fibrosis in a patientcomprising administering an effective amount of the pharmaceuticalcomposition or tablet of the invention to the patient, preferably amammal, wherein the patient possesses the CFTR genetic mutation isselected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549Rand S1251N. In one aspect, the present invention is directed to a methodof treating, lessening the severity of, or symptomatically treatingcystic fibrosis in a patient comprising administering an effectiveamount of the pharmaceutical composition or tablet of the invention tothe patient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from E193K, F1052V and G1069R. In someembodiments of this aspect, the method produces a greater than 10-foldincrease in chloride transport relative to baseline chloride transport.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from R117C, D110H, R347H, R352Q, E56K,P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270Nand D1152H. In one embodiment of this aspect, the method produces anincrease in chloride transport which is greater or equal to 10% abovethe baseline chloride transport.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A,1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A,1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A,4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G,711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A,1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G,IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G. In one aspect, thepresent invention is directed to a method of treating, lessening theseverity of, or symptomatically treating cystic fibrosis in a patientcomprising administering an effective amount of the pharmaceuticalcomposition or tablet of the invention to the patient, preferably amammal, wherein the patient possesses the CFTR genetic mutation isselected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and3849+10kbC->T. In one aspect, the present invention is directed to amethod of treating, lessening the severity of, or symptomaticallytreating cystic fibrosis in a patient comprising administering aneffective amount of the pharmaceutical composition or tablet of theinvention to the patient, preferably a mammal, wherein the patientpossesses the CFTR genetic mutation is selected from 2789+5G->A and3272-26A->G.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P,G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H,R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W,F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A,1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A,1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A,4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G,711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A,1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G,IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTRmutation selected from F508del, R117H, and G551D, and one or more humanCFTR mutations selected from F508del, R117H, and G551D.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P,G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and one or morehuman CFTR mutations selected from F508del, R117H, and G551D. In oneaspect, the present invention is directed to a method of treating,lessening the severity of, or symptomatically treating cystic fibrosisin a patient comprising administering an effective amount of thepharmaceutical composition or tablet of the invention to the patient,preferably a mammal, wherein the patient possesses the CFTR geneticmutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D,S549N, S549R and S1251N, and one or more human CFTR mutations selectedfrom F508del, R117H, and G551D. In one aspect, the present invention isdirected to a method of treating, lessening the severity of, orsymptomatically treating cystic fibrosis in a patient comprisingadministering an effective amount of the pharmaceutical composition ortablet of the invention to the patient, preferably a mammal, wherein thepatient possesses the CFTR genetic mutation is selected from E193K,F1052V and G1069R, and one or more human CFTR mutations selected fromF508del, R117H, and G551D. In some embodiments of this aspect, themethod produces a greater than 10-fold increase in chloride transportrelative to baseline chloride transport.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from R117C, D110H, R347H, R352Q, E56K,P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270Nand D1152H, and one or more human CFTR mutations selected from F508del,R117H, and G551D. In one embodiment of this aspect, the method producesan increase in chloride transport which is greater or equal to 10% abovethe baseline chloride transport.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A,1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A,1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A,4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G,711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A,1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G,IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and one or morehuman CFTR mutations selected from F508del, R117H, and G551D. In oneaspect, the present invention is directed to a method of treating,lessening the severity of, or symptomatically treating cystic fibrosisin a patient comprising administering an effective amount of thepharmaceutical composition or tablet of the invention to the patient,preferably a mammal, wherein the patient possesses the CFTR geneticmutation is selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A,3272-26A->G and 3849+10kbC->T, and one or more human CFTR mutationsselected from. F508del, R117H, and G551D. In one aspect, the presentinvention is directed to a method of treating, lessening the severityof, or symptomatically treating cystic fibrosis in a patient comprisingadministering an effective amount of the pharmaceutical composition ortablet of the invention to the patient, preferably a mammal, wherein thepatient possesses the CFTR genetic mutation is selected from 2789+5G->Aand 3272-26A->G, and one or more human CFTR mutations selected fromF508del, R117H, and G551D.

In one aspect, the present invention is directed to a method oftreating, lessening the severity of, or symptomatically treating cysticfibrosis in a patient comprising administering an effective amount ofthe pharmaceutical composition or tablet of the invention to thepatient, preferably a mammal, wherein the patient possesses the CFTRgenetic mutation selected from FIG. 1.

In certain embodiments, the composition of the present invention isuseful for treating, lessening the severity of, or symptomaticallytreating cystic fibrosis in patients who exhibit residual CFTR activityin the apical membrane of respiratory and non-respiratory epithelia. Thepresence of residual CFTR activity at the epithelial surface can bereadily detected using methods known in the art, e.g., standardelectrophysiological, biochemical, or histochemical techniques. Suchmethods identify CFTR activity using in vivo or ex vivoelectrophysiological techniques, measurement of sweat or salivary Cl⁻concentrations, or ex vivo biochemical or histochemical techniques tomonitor cell surface density. Using such methods, residual CFTR activitycan be readily detected in patients heterozygous or homozygous for avariety of different mutations, including patients homozygous orheterozygous for the most common mutation, F508del, as well as othermutations such as the G551D mutation, or the R117H mutation. In certainembodiments, compositions of the present invention are useful fortreating, lessening the severity of, or symptomatically treating cysticfibrosis in patients who exhibit little to no residual CFTR activity. Incertain embodiments, compositions of the present invention are usefulfor treating, lessening the severity of, or symptomatically treatingcystic fibrosis in patients who exhibit little to no residual CFTRactivity in the apical membrane of respiratory epithelia.

In another embodiment, the compositions of the present invention areuseful for treating or lessening the severity of cystic fibrosis inpatients who exhibit residual CFTR activity using pharmacologicalmethods. In another embodiment, the compositions of the presentinvention are useful for treating or lessening the severity of cysticfibrosis in patients who have residual CFTR activity using gene therapy.Such methods increase the amount of CFTR present at the cell surface,thereby inducing a hitherto absent CFTR activity in a patient oraugmenting the existing level of residual CFTR activity in a patient.

In one embodiment, the compositions of the present invention are usefulfor treating or lessening the severity of cystic fibrosis in patientswithin certain genotypes exhibiting residual CFTR activity, e.g., ClassI mutations (not synthesized), class II mutation (misfolding), class IIImutations (impaired regulation or gating), class IV mutations (alteredconductance), or class V mutations (reduced synthesis).

In one embodiment, compositions of the present invention are useful fortreating, lessening the severity of, or symptomatically treating cysticfibrosis in patients within certain clinical phenotypes, e.g., amoderate to mild clinical phenotype that typically correlates with theamount of residual CFTR activity in the apical membrane of epithelia.Such phenotypes include patients exhibiting pancreatic sufficiency.

In one embodiment, the compositions of the present invention are usefulfor treating, lessening the severity of, or symptomatically treatingpatients diagnosed with pancreatic sufficiency, idiopathic pancreatitisand congenital bilateral absence of the vas deferens, or mild lungdisease wherein the patient exhibits residual CFTR activity.

In one embodiment, the compositions of the present invention are usefulfor treating, lessening the severity of, or symptomatically treatingpatients diagnosed with pancreatic sufficiency, idiopathic pancreatitisand congenital bilateral absence of the vas deferens, or mild lungdisease wherein the patient has wild type CFTR.

In addition to cystic fibrosis, modulation of CFTR activity may bebeneficial for other diseases not directly caused by mutations in CFTR,such as secretory diseases and other protein folding diseases mediatedby CFTR. These include, but are not limited to, chronic obstructivepulmonary disease (COPD), dry eye disease, and Sjögren's Syndrome. COPDis characterized by airflow limitation that is progressive and not fullyreversible. The airflow limitation is due to mucus hypersecretion,emphysema, and bronchiolitis. Activators of mutant or wild-type CFTRoffer a potential treatment of mucus hypersecretion and impairedmucociliary clearance that is common in COPD. Specifically, increasinganion secretion across CFTR may facilitate fluid transport into theairway surface liquid to hydrate the mucus and optimized periciliaryfluid viscosity. This would lead to enhanced mucociliary clearance and areduction in the symptoms associated with COPD. Dry eye disease ischaracterized by a decrease in tear aqueous production and abnormal tearfilm lipid, protein and mucin profiles. There are many causes of dryeye, some of which include age, Lasik eye surgery, arthritis,medications, chemical/thermal burns, allergies, and diseases, such ascystic fibrosis and Sjögrens's syndrome. Increasing anion secretion viaCFTR would enhance fluid transport from the corneal endothelial cellsand secretory glands surrounding the eye to increase corneal hydration.This would help to alleviate the symptoms associated with dry eyedisease. Sjögrens's syndrome is an autoimmune disease in which theimmune system attacks moisture-producing glands throughout the body,including the eye, mouth, skin, respiratory tissue, liver, vagina, andgut. Symptoms, include, dry eye, mouth, and vagina, as well as lungdisease. The disease is also associated with rheumatoid arthritis,systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis.Defective protein trafficking is believed to cause the disease, forwhich treatment options are limited. Augmenters or inducers of CFTRactivity may hydrate the various organs afflicted by the disease andhelp to elevate the associated symptoms.

In one embodiment, the invention relates to a method of augmenting orinducing anion channel activity in vitro or in vivo, comprisingcontacting the channel with a composition of the present invention. Inanother embodiment, the anion channel is a chloride channel or abicarbonate channel. In another embodiment, the anion channel is achloride channel.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “patient”, as used herein, means ananimal, preferably a mammal, and most preferably a human.

In recent years a number of attempts have been made to treat cysticfibrosis using gene therapy. Gene therapy is the insertion, alteration,or removal of genes within an individual's cells and biological tissuesto treat disease. It is a technique for correcting defective genes thatare responsible for disease development. The most common form of genetherapy involves the insertion of functional genes into an unspecifiedgenomic location in order to replace a mutated gene, but other formsinvolve directly correcting the mutation or modifying normal gene thatenables a viral infection. Although the technology is still in itsinfancy, it has been used with some success.

Cystic fibrosis is a good candidate for gene therapy as it is primarilycaused by mutations in a single gene. A normal copy of the gene could bedelivered to patients via topical delivery to the lung, not requiringinvasive techniques or surgery. A gene complementation approach wouldaslo directly target the cause of the disease and could correct manyaspects of the complex lung pathology.

Soon after the cloning of the CFTR gene, proof-of-principle wasestablished when the Cl-conductance defect was corrected after deliveryof a functional copy of human wild-type CFTR DNA to cells isolated fromcystic fibrosis patients. To date, a number of trials for cysticfibrosis gene therapy have been tested in humans. These early studieswere concerned mainly with safety issues.

In one embodiment, the invention features a method of treating cysticfibrosis comprising administering to the patient a compound of formula Ito Id in conjunction with gene therapy. The gene therapy can be asdisclosed in Internation Published Patent Application No. WO2013061091,incorporated herein in its entirety by reference. Administration may beprior, concomitant, or subsequent administration of a compound offormula I-Id, or any of the pharmaceutical compositions of the presentinvention.

In another embodiment, the gene therapy features administering to thepatient 1 mL to less than 10 mLs of a complex of (i) a non-viral CpGdinucleotide-free plasmid comprising nucleic acid encoding a CFTRpolypeptide operatively linked to hCEF1 promoter, wherein the plasmid isat a concentration of 2 mg/mL to 3 mg/mL, and (ii) GL67A lipid mixtureat a concentration of 10 mg/mL to 20 mg/mL.

In one embodiment, gene therapy is administered to a patient with cysticfibrosis prior, concomitant, or subsequent administration of apharmaceutical composition comprising (i) a compound of formula I-Id and(ii) 3-(6-(1-(2,2-difluorobenzo[d][1,3[dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.

In one embodiment, gene therapy is administered to a patient with cysticfibrosis prior, concomitant, or subsequent administration of apharmaceutical composition comprising (i) a compound of formula I-Id and(ii)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.

In one embodiment, gene therapy is administered to a patient with cysticfibrosis prior, concomitant, or subsequent administration of apharmaceutical composition comprising (i) a compound of formula I-Id and(ii)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid.

In one embodiment, gene therapy is administered to a patient with cysticfibrosis prior, concomitant, or subsequent administration of apharmaceutical composition comprising (i) a compound of formula I-Id;(ii) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and (iii)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In one embodiment, gene therapy is administered to a patient with cysticfibrosis prior, concomitant, or subsequent administration of apharmaceutical composition comprising (i) a compound of formula I-Id;(ii)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;and (iii)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In one embodiment, gene therapy is administered to a patient with cysticfibrosis prior, concomitant, or subsequent administration of apharmaceutical composition comprising (i) a compound of formula I-Id;(ii)4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid; and (iii)N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

Kits

In another aspect, the present invention features a kit comprising acompound and/or pharmaceutical composition of the present invention andinstructions for use thereof.

In another embodiment, the kits of the present invention furthercomprise one or more additional therapeutic agent(s). In anotherembodiment, the additional therapeutic agent is selected from amucolytic agent, bronchodialator, an antibiotic, an anti-infectiveagent, a CFTR modulator, or an anti-inflammatory agent. In anotherembodiment, the additional therapeutic agent is a CFTR modulator. Inanother embodiment, the additional therapeutic agent is a CFTRcorrector.

In another embodiment, the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the additional therapeutic agent is a CFTRpotentiator.

In another embodiment, the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the additional therapeutic agents are a CFTRcorrector and a CFTR potentiator.

In another embodiment, the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

In another embodiment, the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

In another embodiment, the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

In another embodiment, the kits of the present invention are drawn tokits wherein the compounds or the pharmaceutical compositions of thepresent invention and the one or more additional therapeutic agent(s)are in separate containers.

In another embodiment, the kits of the present invention are drawn tokits wherein the compounds or the pharmaceutical compositions of thepresent invention and the one or more additional therapeutic agent(s)are in the same container.

In another embodiment, the container is a bottle, vial, or blister pack,or combination thereof.

Anywhere in the present application where a name of a compound may notcorrectly describe the structure of the compound, the structuresupersedes the name and governs.

EXAMPLES PREPARATION 1:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carboxamide(Compound 26) Step 1: 6-tert-butyl-2-chloro-pyridine-3-carbonitrile

2,2-Dimethylpropanoic acid (50. mL, 870 mmol),2-chloropyridine-3-carbonitrile (30 g, 220 mmol) and AgNO₃ (9.2 g, 54mmol) were suspended in 10% aq. H₂SO₄ (300 mL). A solution of ammoniumperoxydisulfate (91 g, 430 mmol) and water (480 mL) was added to themixture dropwise through an addition funnel. The mixture was stirred atroom temperature overnight. The pH of reaction mixture was adjusted to˜8-9 with 30% NH₄OH (˜250 mL) and the mixture was extracted with ethylacetate (3×300 mL). The combined organic layers were washed with brine,dried over sodium sulfate, and concentrated. The residue was subjectedto silica gel column chromatography (0-25% ethyl acetate/hexanes) togive 6-tert-butyl-2-chloro-pyridine-3-carbonitrile (37 g, 83%) as aclear oil which solidified upon standing. ¹H NMR (400 MHz, CDCl₃) δ 7.83(d, J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 1.29 (s, 9H). ESI-MS m/zcalc. 194.1, found 195.0 (M+1)⁺; Retention time: 1.66 min (3 min run).

Step 2: 6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carbonitrile

A mixture of 6-tert-butyl-2-chloro-pyridine-3-carbonitrile (400. mg,2.06 mmol), (2,4,6-trimethylphenyl)boronic acid (506 mg, 3.08 mmol),Pd(dppf)₂Cl₂*CH₂Cl₂ (75 mg, 0.10 mmol), NaHCO₃ (173 mg, 2.06 mmol) andDME (2 mL) was heated at 120° C. in a microwave reactor for 30 min. Themixture was partitioned between CH₂Cl₂ and water. The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂ (2×). Thecombined organics were dried over sodium sulfate, filtered andconcentrated. The residue was subjected to silica gel columnchromatography (0-20% ethyl acetate/hexanes) to give6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carbonitrile (225 mg,39%). ESI-MS m/z calc. 278.2, found 279.4 (M+1)⁺; Retention time: 0.84mM (3 min run).

Step 3: 6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carboxylic acid

A mixture of6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carbonitrile (225 mg,0.808 mmol), KOH (2.0 mL of 4.0 M, 8.0 mmol) and EtOH (2.3 mL) washeated at 90° C. for 2.5 d. The mixture was acidified with conc. HCl to˜pH 2 before it was concentrated under reduced pressure. The residue wassubjected to preparatory-HPLC (10-99% acetonitrile/water with 0.05 mMHCl) to give 6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carboxylicacid (40 mg, 17%) as a white solid. ESI-MS m/z calc. 297.2, found 298.4(M+1)⁺; Retention time: 1.77 min (3 min run).

Step 4:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carboxamide(Compound 26)

Sodium (3-nitrophenyl)sulfonylazanide (60. mg, 0.27 mmol) was added to amixture of 6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carboxylicacid (40. mg, 0.13 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylenei-N-methylmethanaminiumhexafluorophosphate N-oxide (51 mg, 0.13 mmol) and N,N-dimethylformamide(800.0 μL) at room temperature. The mixture was allowed to stir at 70°C. overnight before it was filtered and subjected to preparatory-HPLC(10-99% acetonitrile/water with 0.05% HCl) to give the nitrointermediate,6-tert-butyl-N-(3-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenyl)pyridine-3-carboxamide.The nitro intermediate was taken up in acetic acid (1 mL) before Zn (8.8mg, 0.13 mmol) was added. The mixture was stirred at room temperaturefor 30 min before it was filtered. The filtrate was subjected topreparatory-HPLC (10-99% acetonitrile/water with 0.05 mM HCl) to giveN-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenyl)pyridine-3-carboxamide(Compound 26) (13 mg, 22%). ESI-MS m/z calc. 451.2, found 452.5 (M+1)⁺;Retention time: 1.81 min (3 min run).

PREPARATION 2:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-chlorophenyl)pyridine-3-carboxamide(Compound 223) Step 1: 6-tert-butyl-2-chloro-pyridine-3-carboxamide

To a mixture of 6-tert-butyl-2-chloro-pyridine-3-carbonitrile (6.81 g,35.0 mmol) and NaOH (38.5 mL of 1.0 M, 38.5 mmol) in EtOH (175 mL) wasslowly added hydrogen peroxide (19.9 mL of 30% w/v, 175 mmol). Thereaction mixture was stirred at room temperature for 45 min. beforeadditional hydrogen peroxide (19.9 mL of 30% w/v, 175 mmol) was added.After 1 h, the mixture was slowly quenched with saturated sodiumbisulfite solution, diluted with water, and extracted with ethylacetate. The combined extracts were washed with water, dried over sodiumsulfate, and evaporated to give6-tert-butyl-2-chloro-pyridine-3-carboxamide (7.21 g, 97%) as a whitesolid. ESI-MS m/z calc. 212.1, found 212.9 (M+1)⁺; Retention time: 0.46min (1 min run).

Step 2:6-tert-butyl-2-chloro-N-(3-nitrophenyl)sulfonyl-pyridine-3-carboxamide

To a solution of 6-(tert-butyl)-2-chloronicotinamide (3.19 g, 15.0 mmol)and 3-nitrobenzenesulfonyl chloride (3.32 g, 15.0 mmol) in THF (100.0mL) was slowly added NaH (1.80 g, 60%, w/w, 45.0 mmol) in portions. Themixture was allowed to stir for 2 h at room temperature before it wasquenched with saturated aqueous ammonium chloride solution. The mixturewas extracted with ethyl acetate (3×). The combined extracts were washedwith water, dried over sodium sulfate, and evaporated. The residue wastaken up in diethyl ether. The solids were filtered, washed with diethylether, and dried under vacuum. The filtrate was evaporated and theresidue was purified by silica gel chromatography (1-11%methanol/CH₂Cl₂). The two batches (solid from ether and product fromcolumn) were combined to give6-(tert-butyl)-2-chloro-N-((3-nitrophenyl)sulfonyl)nicotinamide (3.56 g,60%) as light yellow solid. ESI-MS m/z calc. 397.1, found 398.0 (M+1)⁺;Retention time: 0.66 min (1 min run).

Step 3:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-chloro-pyridine-3-carboxamide

To a solution of6-(tert-butyl)-2-chloro-N((3-nitrophenyl)sulfonypnicotinamide (1.40 g,3.52 mmol) in glacial acetic acid (140 mL) was added zinc (5.76 g, 88.0mmol). The reaction mixture was allowed to stir at room temperature for1 h before it was filtered and concentrated under reduced pressure. Thecrude product was subjected silica gel column chromatography (0-5%methanol/CH₂Cl₂) to provideN-(3-aminophenyl)sulfonyl-6-tert-butyl-2-chloro-pyridine-3-carboxamide(1.12 g, 87%) as an orange sticky foam. ESI-MS m/z calc. 367.1, found368.6 (M+1)⁺; Retention time: 1.09 min (3 min run).

Step 4:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-chlorophenyl)pyridine-3-carboxamide(Compound 223)

To (4-chlorophenyl)boronic acid (26 mg, 0.16 mmol) was added a solutionofN-(3-aminophenyl)sulfonyl-6-tert-butyl-2-chloro-pyridine-3-carboxamide(50. mg, 0.14 mmol) in DMA (0.5 mL). Na₂CO₃ (136 μL, 2.0 M, 0.27 mmol)and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (5 mg, 0.007 mmol) were added and the vessel wassealed under nitrogen gas and heated under microwave irradiation at 120°C. for 20 minutes. The reaction mixture was cooled to room temperature,filtered and subjected to preparatory-HPLC (10-99% water/CH₃CN with 0.05mM HCl) to giveN-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-chlorophenyl)pyridine-3-carboxamide(Compound 223) (15 mg, 25%). ESI-MS m/z calc. 443.1, found 444.1 (M+1)⁺;Retention time: 1.81 min (3 min run).

The following compounds were synthesized using the procedures describedherein:

-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-tert-butylphenyl)pyridine-3-carboxamide    (Compound 252),-   N-(3-aminophenyl)sulfonyl-8,8-dimethyl-2-phenyl-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 685),-   (3-aminophenyl)sulfonyl-[8,8-dimethyl-2-(p-tolyl)-6,7-dihydro-5H-quinoline-3-carbonyl]azanide    (Compound 1231),-   N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-(cyclohexen-1-yl)pyridine-3-carboxamide    (Compound 880),-   N-(4-aminophenyl)sulfonyl-8,8-dimethyl-2-phenyl-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 1190),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(4-fluorophenyl)pyridine-3-carboxamide    (Compound 417),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-indan-5-yl-pyridine-3-carboxamide    (Compound 308),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(3,4-dimethylphenyl)pyridine-3-carboxamide    (Compound 274),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(3-tert-butylphenyl)pyridine-3-carboxamide    (Compound 229),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(3,5-dimethylphenyl)pyridine-3-carboxamide    (Compound 52),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-isopropylphenyl)pyridine-3-carboxamide    (Compound 314),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-ethylphenyl)pyridine-3-carboxamide    (Compound 359),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide    (Compound 129),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(3-fluoro-5-methyl-phenyl)pyridine-3-carboxamide    (Compound 237),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 301),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-fluoro-3-methyl-phenyl)pyridine-3-carboxamide    (Compound 177),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(3-fluoro-4-methyl-phenyl)pyridine-3-carboxamide    (Compound 349),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4-dimethylphenyl)pyridine-3-carboxamide    (Compound 5),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(m-tolyl)pyridine-3-carboxamide    (Compound 282),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-fluorophenyl)pyridine-3-carboxamide    (Compound 46),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2-fluoro-5-methyl-phenyl)pyridine-3-carboxamide    (Compound 1350) (Commpound 1350),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(3,4-difluorophenyl)pyridine-3-carboxamide    (Compound 1217),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(o-tolyflpyridine-3-carboxamide    (Compound 1036),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-methoxyphenyl)pyridine-3-carboxamide    (Compound 550),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2-fluoro-4-methyl-phenyl)pyridine-3-carboxamide    (Compound 1331),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-phenyl-pyridine-3-carboxamide    (Compound 542), and-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(3,4-difluorophenyl)pyridine-3-carboxamide    (Compound 1217).

PREPARATION 3:N-(benzenesulfonyl)-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide(Compound 74) Step 1: 6-tert-butyl-2-chloro-pyridine-3-carboxylic acid

A solution of KOH (8.65 g, 154 mmol) in water (25 mL) was added to asolution of 6-tert-butyl-2-chloro-pyridine-3-carbonitrile (5.00 g, 25.7mmol) in isopropanol (25 mL). The reaction mixture was allowed to stirat 90° C. overnight. After cooling to room temperature, the reactionmixture was diluted with ethyl acetate (75 mL) and was extracted withaqueous NaOH (1 N, 3×75 mL). The combined aqueous layers were acidifiedto pH 3 with the addition of aqueous HCl (1 N, 200 mL) and wereextracted with ethyl acetate (2×75 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated to give6-tert-butyl-2-chloro-pyridine-3-carboxylic acid (5.25 g, 96%) as ayellow solid. ESI-MS m/z calc. 213.1, found 214.4 (M+1)⁺; Retentiontime: 1.09 min (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 10.39 (s, 1H),8.26 (d, J=8.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 1.38 (s, 9H).

Step 2: 6-tert-butyl-2-(p-tolyl)pyridine-3-carboxylic acid

6-tert-Butyl-2-chloro-pyridine-3-carboxylic acid (1.35 g, 6.32 mmol) andp-tolylboronic acid (1.03 g, 7.58 mmol) were suspended in DMA (14 mL).Aqueous sodium carbonate (6.3 mL of 2.0 M, 13 mmol) was added followedby dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (231 mg, 0.312 mmol). The reaction vessel wassealed under nitrogen and heated to 140° C. for 1.5 h in a microwavereactor. The reaction mixture was diluted with ethyl acetate (50 mL) andwas washed with aqueous NaOH (1 M, 4×50 mL). The combined aqueous layerswere acidified to pH 3 with 1 N HCl and then extracted with ethylacetate (5×50 mL). The organic layers were combined, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography (0-30% ethylacetate/hexane) to give 6-tert-butyl-2-(p-tolyl)pyridine-3-carboxylicacid (740 mg, 43%) as a white solid. ESI-MS m/z calc. 269.1, found 270.5(M+1)⁺; Retention time: 1.53 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed above:8,8-dimethyl-2-(p-tolyl)-5,6,7,8-tetrahydroquinoline-3-carboxylic acid.

Step 3:N-(benzenesulfonyl)-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide(Compound 74)

To benzenesulfonamide (23 mg, 0.14 mmol) was added6-tert-butyl-2-(p-tolyl)pyridine-3-carboxylic acid (35 mg, 0.13 mmol) inN,N-dimethylformamide (400 μL). A solution ofN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (54 mg, 0.14 mmol) in N,N-dimethylformamide(125 μL) was added followed by solid potassium carbonate (54 mg, 0.39mmol). The reaction mixture was allowed to stir at 80° C. for 1 h.AdditionalN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylenel-N-methylmethanaminiumhexafluorophosphate N-oxide (0.5 eq) was added and the reaction mixturewas allowed to stir overnight at 80° C. The mixture was cooled, filteredand subjected to preparatory-HPLC (10-99% water/acetonitrile with 0.05mM HCl) to giveN-(benzenesulfonyl)-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide(Compound 74) (28 mg, 53%). ESI-MS m/z calc. 408.2, found 409.3 (M+1)⁺;Retention time: 1.93 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   6-tert-butyl-N-(3-ethylphenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 50),-   6-tert-butyl-N-(3-methoxyphenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 327),-   6-tert-butyl-N-(4-methoxyphenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 206),-   6-tert-butyl-N-(4-cyanophenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 288),-   6-tert-butyl-2-(p-tolyl)-N-(2-pyridylsulfonyl)pyridine-3-carboxamide    (Compound 407),-   6-tert-butyl-2-(p-tolyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 632),-   6-tert-butyl-N-[(5-methyl-2-pyridyl)sulfonyl]-2-(p-tolyl)pyridine-3-carboxamide    (Compound 1355),-   6-tert-butyl-N-(2-cyanophenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 623),-   6-tert-butyl-N-(2-methoxyphenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 1124),-   N-(4-aminophenyl)sulfonyl-8,8-dimethyl-2-(p-tolyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 1307),-   6-tert-butyl-N-(2-hydroxyphenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 1175),-   N-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(p-tolyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 444),-   8,8-dimethyl-2-(p-tolyl)-N-(1H-pyrazol-5-ylsulfonyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 1292),-   6-tert-butyl-N-(4-hydroxyphenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 809),-   6-tert-butyl-N-(3-hydroxyphenyl)sulfonyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 1265),-   6-tert-butyl-N-[(6-methoxy-3-pyridyl)sulfonyl]-2-(p-tolyl)pyridine-3-carboxamide    (Compound 512),-   N-[(6-amino-3-pyridyl)sulfonyl]-8,8-dimethyl-2-(p-tolyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 635),-   6-(3-fluoro-5-isopropoxy-phenyl)-2-(p-tolyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 849),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isopropoxy-phenyl)-2-(p-tolyl)pyridine-3-carboxamide    (Compound 722),-   6-(3-fluoro-5-isopropoxy-phenyl)-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-(p-tolyl)pyridine-3-carboxamide    (Compound 798),-   6-tert-butyl-N-(1H-pyrazol-4-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 401),-   6-(4-fluorophenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 518),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 423),-   6-tert-butyl-N-I[6-(difluoromethyl)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 501),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-2,6-bis(p-tolyl)pyridine-3-carboxamide    (Compound 524),-   6-(6-methoxy-5-methyl-3-pyridyl)-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-(p-tolyl)pyridine-3-carboxamide    (Compound 861),-   6-tert-butyl-N-[(6-methoxy-2-pyridyl)sulfonyl]-2-(p-tolyl)pyridine-3-carboxamide    (Compound 75), and-   N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 297).

PREPARATION 4:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide(Compound 58) Step 1:6-tert-butyl-N-[(6-fluoro-2-pyridyl)sulfonyl]-2-(p-tolyl)pyridine-3-carboxamide

N,N-diisopropyl ethyl amine (104 μL, 0.5940 mmol) was added to a mixtureof 6-tert-butyl-2-(p-tolyl)pyridine-3-carboxylic acid (80. mg, 0.30mmol), 6-fluoropyridine-2-sulfonamide (58 mg, 0.33 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylenel-N-methylmethanarniniumhexafluorophosphate N-oxide (136 mg, 0.356 mmol) andN,N-dimethylformamide (800 μL) at room temperature. The mixture washeated at 70° C. overnight before it was cooled. The mixture waspartitioned between ethyl acetate and 1N HCl. The layers were separatedand the aqueous layer was extracted with ethyl acetate (3×). Thecombined organics were washed with brine, dried over sodium sulfate,filtered, and concentrated. The residue was subjected to silica gelcolumn chromatography (0-20% ethyl acetate/hexanes) to give6-tert-butyl-N-[(6-fluoro-2-pyridyl)sulfonyl]-2-(p-tolyl)pyridine-3-carboxamide(66 mg, 38%) as a yellowish solid. ESI-MS m/z calc. 427.1, found 428.4(M+1)⁺; Retention time: 0.7 min (1 min run).

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide(Compund 58)

A mixture of6-tert-butyl-N-[(6-fluoro-2-pyridyl)sulfonyl]-2-(p-tolyl)pyridine-3-carboxamide(55 mg, 0.13 mmol) and NH₄OH (30%, 860 μL) was heated at 150° C. for 30min in a microwave reactor. The mixture was concentrated and the residuewas subjected to preparatory-HPLC (10-99% acetonitrile/water with 0.05mM HCl) to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide(Compound 58) (17 mg, 31%). ESI-MS m/z calc. 424.2, found 425.4 (M+1)⁺;Retention time: 1.63 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(m-tolyl)pyridine-3-carboxamide    (Compound 31),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(cyclopenten-1-yl)pyridine-3-carboxamide    (Compound 529),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(cyclohexen-1-yl)pyridine-3-carboxamide    (Compound 478),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethox    yphenyl)-2-(p-tolyl)pyridine-3-carboxamide (Compound 409),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(4-fluorophenyl)pyridine-3-carboxamide    (Compound 417),-   and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-phenyl-pyridine-3-carboxamide    (Compound 334).

PREPARATION 5:6-phenethyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid Step 1:methyl 6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate

NaH (60%, 2.13 g, 53.3 mmol) was added to a solution of2,4,6-trimethylphenol (6.60 g, 48.5 mmol) and N,N-dimethylformamide (150mL) at 0° C. The mixture was stirred for 15 min before a solution ofmethyl 2,6-dichloronicotinate (10.0 g, 48.5 mmol) inN,N-dimethylformamide (20 mL) was added dropwise. The mixture wasallowed to stir for 1 h at room temperature before water was added. Themixture was extracted with ethyl acetate (2×). The combined extractswere washed with water and brine, dried over sodium sulfate, filteredand concentrated. The residue was subjected to silica gel columnchromatography (0-50% CH₂Cl₂/hexanes) to give methyl6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (3.58 g, 24%).ESI-MS m/z calc. 305.1, found 306.2 (M+1)⁺; Retention time: 0.87 min (1min run).

Step 2: methyl6-phenethyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate

Bromo-(2-phenylethyl)zinc (3.9 mL of 0.5 M, 2.0 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethaneadduct (36 mg, 0.049 mmol) were stirred at room temperature under anatmosphere of nitrogen for 20 min. Methyl6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (150 mg, 0.49mmol) was added to the reaction mixture and it was then heated at 150°C. for 10 minutes in a microwave reactor. A saturated aqueous solutionof ethylenediaminetetraacetic acid disodium salt (2 mL) and a saturatedaqueous solution of ammonium chloride were added to the reactionmixture. After stirring for 30 minutes, the layers were separated andthe aqueous layer was extracted with dichloromethane. The combinedorganic layers were evaporated to dryness and the residue was subjectedto preparatory-HPLC (20-80% acetonitrile/water with 5 mM HCl) to yieldmethyl6-(2-phenylethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (56mg, 31%). ESI-MS m/z calc. 375.2, found 376.4 (M+1)⁺; Retention time:0.87 min (1 min run).

Step 3: 6-phenethyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid

Methyl6-(2-phenylethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (56mg, 0.15 mmol) was dissolved in methanol (5mL). NaOH (245 μL of 4.0 M,0.98 mmol) was added and the mixture was stirred at room temperatureovernight. The solvent was removed and the pH of the residue wasadjusted to ˜3 with 1N HCl. The precipitate was filtered, washed withwater and dried to give6-phenethyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (21 mg,36%). ESI-MS m/z calc. 361.2, found 362.5 (M+1)⁺; Retention time: 0.77min (1 min run).

The following compound can be synthesized using the procedures describedherein: 6-benzyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid.

PREPARATION 6:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228) Step 1:6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonitrile

6-tert-Butyl-2-chloro-pyridine-3-carbonitrile (5.00 g, 25.7 mmol),2,4,6-trimethylphenol (3.50 g, 25.7 mmol), K₂CO₃ (3.91 g, 28.3 mmol) andN,N-dimethylformamide (10 mL) were added to a 40 mL vial. The mixturewas stirred overnight at 95° C. The reaction mixture was diluted withH₂O (10 mL) and was extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography (0-20% ethyl acetate/hexanes) to give6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonitrile (6.70 g,84%) as a white solid. ESI-MS m/z calc. 294.2, found 295.2 (M+1)⁺;Retention time: 2.31 min (3 min run). ¹H NMR (400 MHz, DMSO) δ 8.31 (d,J=8.0 Hz, 1H), 7.25 (d, J=7.9 Hz, 1H), 6.96 (s, 2H), 2.27 (s, 3H), 2.00(s, 6H), 1.07 (s, 9H).

Step 2: 6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylicacid

A mixture of6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonitrile (4.50 g,15.3 mmol), KOH (5.15 g, 91.7 mmol), EtOH (135 mL) and H₂O (32 mL) washeated at 90° C. overnight. Additional KOH (2.00 g, 35.6 mmol) was addedand the mixture was heated at 90° C. overnight. The mixture was cooledto room temperature, concentrated and acidified to pH ˜2 with 2N HCl.The solids were collected via filtration and were placed in a vacuumoven at 50° C. overnight to give6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (4.64g, 96%). ¹H NMR (400 MHz, DMSO) δ 8.14 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.8Hz, 1H), 6.91 (s, 2H), 2.26 (s, 3H), 1.97 (s, 6H), 1.04 (s, 9H).

Step 3:6-tert-butyl-N4(6-fluoro-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

N-ethyl-N-isopropylpropan-2-amine (560 μL, 3.19 mmol) was added to amixture of 6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylicacid (500. mg, 1.56 mmol), 6-fluoropyridine-2-sulfonamide (309 mg, 1.76mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (728 mg, 1.91 mmol) andN,N-dimethylformamide (5 mL) at room temperature. The mixture was heatedat 70° C. overnight before it was cooled. The mixture was partitionedbetween ethyl acetate and 1N HCl. The layers were separated and theaqueous layer was extracted with ethyl acetate (3×). The combinedorganics were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was subjected to silica gel columnchromatography (0-20% ethyl acetate/hexanes), then a second purificationby silica gel column chromatography (0-10% ethyl acetate/hexanes) togive6-tert-butyl-N-[(6-fluoro-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(230 mg, 23%) as a white solid. ESI-MS m/z calc. 471.2, found 472.4(M+1)⁺; Retention time: 2.32 min (3 min run).

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228)

6-tert-Butyl-N-[(6-fluoro-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(77 mg, 0.16 mmol) was dissolved in ammonium hydroxide (10 mL of 30%w/w) and irradiated in the microwave reactor for 1 h at 150° C. Themixture was evaporated and the crude material was purified bypreparatory-HPLC (10-99% acetonitrile/water with 5 μM HCl). The materialwas further purified by silica gel chromatography (0-100% ethylacetate/hexanes) to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 228) (27 mg, 35%). ¹H NMR (400 MHz, DMSO) δ 12.10 (s, 1H),8.01 (d, J=7.8 Hz, 1H), 7.67-7.58 (m, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.11(d, J=7.9 Hz, 1H), 6.90 (s, 2H), 6.69 (d, J=8.6 Hz, 1H), 6.49 (s, 2H),2.26 (s, 3H), 1.97 (s, 6H), 1.05 (s, 9H). ESI-MS m/z calc. 468.2, found469.3 (M+1)⁺; Retention time: 2.11 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   6-tert-butyl-N-(1H-indol-4-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 275),-   N-(benzenesulfonyl)-6-tert-butyl-2-(2-isopropylphenoxy)pyridine-3-carboxamide    (Compound 147),-   6-tert-butyl-N-[(6-(dimethylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 468),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,1,2,2,2-pentafluoroethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 853),-   N-(4-aminophenyl)sulfonyl-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1297),-   N-(2-aminothiazol-4-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1294),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1310),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 854),-   N-(3-aminophenyl)sulfonyl-6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 826),-   6-(3-fluoro-5-isopropoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 914),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-prop-1-ynyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1172),-   6-tert-butyl-N-(2-methylpyrazol-3-yl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 911),-   N-[(6-amino-2-pyridyl)sulfonyl]-5,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 841),-   N-[[6-(2-hydroxyethylamino)-2-pyridyl]sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 595),-   N-[[6-(dimethylamino)-2-pyridyl]sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 869),-   N-[[6-(2-aminoethylamino)-2-pyridyl]sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1027),-   N-[(6-(methylamino)-2-pyridyl]sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1032),-   N-[[6-(2-dimethylaminoethylamino)-2-pyridyl]sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1122),-   N-[(6-cyano-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 771),-   N-[(6-amino-2-pyridyl)sulfonyl]-4-methyl-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1102),-   6-tert-butyl-N-[[6-(2-hydroxyethylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 916),-   6-tert-butyl-N-[[6-(2-dimethylaminoethylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 947),-   6-[[6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonyl]sulfamoyl]pyridine-2-carboxylic    acid (Compound 461),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-(hydroxymethyl)-2-pyridyl]sulfonyl]-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1340),-   N-[[6-(2-aminoethylamino)-2-pyridyl]sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1054),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1137),-   N-(2-azidophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide,-   6-methyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 670),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-phenethyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1253),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(trifluoromethyl)cyclopropyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 621),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-benzyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1233),-   N-[(6-(isopropylamino)-2-pyridyl]sulfonyl]-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 482),-   N-[(6-(2-methoxyethylamino)-2-pyridyl]sulfonyl]-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (compound 372),-   N-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 182),-   N-(benzenesulfonyl)-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 341),-   6-tert-butyl-N-[3-(methylamino)phenyl]sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 289),-   6-tert-butyl-N-[3-(dimethylamino)phenyl]sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 311),-   6-tert-butyl-N-(2-cyanophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 78),-   N-(benzenesulfonyl)-6-tert-butyl-2-(1-methylindol-7-yl)oxy-pyridine-3-carboxamide    (Compound 326),-   6-tert-butyl-N-(1-methylindol-4-yl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 146),-   N-[(6-amino-5-fluoro-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide,-   6-tert-butyl-N-[(6-methoxy-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 34),-   6-tert-butyl-N-(4-pyridylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 117),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 235),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 590),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylphenoxy)pyridine-3-carboxamide    (Compound 778),-   6-tert-butyl-N-(2-methoxyphenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 115),-   6-tert-butyl-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 191),-   6-tert-butyl-N-(2-pyridylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 222),-   N-[(2-amino-4-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 283),-   6-tert-butyl-N-[(2-methoxy-4-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 217),-   6-tert-butyl-N-(3-pyridylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 330),-   6-tert-butyl-N-(3-methoxyphenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 56),-   N-(benzenesulfonyl)-6-(trifluoromethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 244),-   6-tert-butyl-N-[(3-methoxy-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 92),-   N-(benzenesulfonyl)-2-benzyloxy-6-tert-butyl-pyridine-3-carboxamide    (Compound 130),-   6-tert-butyl-2-(2,4-dimethylphenoxy)-N-[(2-methoxy-3-pyridyl)sulfonyl]pyridine-3-carboxamide    (Compound 89),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4-dimethylphenoxy)pyridine-3-carboxamide    (Compound 204),-   N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 11),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(1-phenylethoxy)pyridine-3-carboxamide    (Compound 219),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)-5,6,7,8-tetrahydroquinoline-3-carboxamide    (Compound 285),-   N-[(5-amino-3-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 163),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2-methylphenoxy)pyridine-3-carboxamide    (Compound 296),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(4-cyano-2,6-dimethyl-phenoxy)pyridine-3-carboxamide    (Compound 111),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4-dimethylphenoxy)pyridine-3-carboxamide    (Compound 251),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethylcyclopentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 503),-   N-(benzenesulfonyl)-6-tert-butyl-2-(3-methoxyphenoxy)pyridine-3-carboxamide    (Compound 101),-   6-tert-butyl-N-[(6-oxo-11/-pyridin-2-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 305),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2-cyano-4,6-dimethyl-phenoxy)pyridine-3-carboxamide    (Compound 221),-   N-(3-aminophenyl)sulfonyl-2-(2,6-dimethylphenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide    (Compound 243),-   N-(3-aminophenyl)sulfonyl-6-(trifluoromethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 96),-   6-tert-butyl-N-[(4-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 107),-   N-(benzenesulfonyl)-5-tert-butyl-2-(2-pyridylmethoxy)pyridine-3-carboxamide    (Compound 154),-   6-tert-butyl-N-[(2-oxo-1H-pyridin-4-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 113),-   6-tert-butyl-2-(2,4-dimethylphenoxy)-N-[(2-hydroxy-3-pyridyl)sulfonyl]pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(trifluoromethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 175),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide    (Compound 246),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-cyclopropyl-4-(trifluoromethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 54),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-phenoxy-pyridine-3-carboxamide    (Compound 272),-   N-(3-aminophenyl)sulfonyl-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 13),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methylcyclopentoxy)pyridine-3-carboxamide    (Compound 452),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-isobutoxy-phenyl)-2-phenoxy-pyridine-3-carboxamide    (Compound 376),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(3-fluorophenyl)ethoxy]pyridine-3-carboxamide    (Compound 562),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3-ethyloxetan-3-yl)methoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 618),-   N-[[6-(3-aminopropylamino)-2-pyridyl]sulfonyl]-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 982),-   N-[[6-(cyclopropylamino)-2-pyridyl]sulfonyl]-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 594),-   6-methyl-N-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 646),-   N-[[6-(2-aminoethylamino)-2-pyridyl]sulfonyl]-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 792),-   6-methyl-N-[(6-morpholino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 883),-   6-methyl-N-[[6-(4-methylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1018),-   N-[[6-(dimethylamino)-2-pyridyl]sulfonyl]-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1250),-   2-(2,4-dimethylphenoxy)-N-[(2-methoxy-3-pyridyl)sulfonyl]-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 1347),-   2-(2,4-dimethylphenoxy)-8,8-dimethyl-N-(1H-pyrazol-3-ylsulfonyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 1246),-   6-tert-butyl-N-[(2-methoxy-6-methyl-3-pyridyl)sulfonyl}-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1153),-   8,8-dimethyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 715),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(oxetan-2-ylmethoxy)pyridine-3-carboxamide    (Compound 640),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(cyclohexoxy)pyridine-3-carboxamide    (Compound 649),-   2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 671),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-phenoxy-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 679),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-tetrahydropyran-3-yloxy-pyridine-3-carboxamide    (Compound 706),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylphenoxy)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 738),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methylphenoxy)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 758),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2-cyano-4,6-dimethyl-phenoxy)pyridine-3-carboxamide    (Compound 767),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,2-difluorocyclopropyl)methoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 769),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(o-tolypethoxy]pyridine-3-carboxamide    (Compound 782),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3-methyloxetan-3-yl)methoxy]pyridine-3-carboxamide    (Compound 824),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4-difluorophenoxy)pyridine-3-carboxamide    (Compound 829),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(4-fluorophenyl)ethoxy]pyridine-3-carboxamide    (Compound 867),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(oxetan-3-yloxy)pyridine-3-carboxamide    (Compound 872),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-phenylethoxy)pyridine-3-carboxamide    (Compound 874),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,2-dimethylcyclopropyl)methoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 894),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(tetrahydropyran-4-ylmethoxy)pyridine-3-carboxamide    (Compound 933),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-difluorocyclohexoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 961),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methyl-2-phenyl-ethoxy)pyridine-3-carboxamide    (Compound 967),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylcyclohexoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 978),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2-isopropylphenoxy)pyridine-3-carboxamide    (Compound 1031),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(1-phenylpropoxy)pyridine-3-carboxamide    (Compound 1045),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-phenoxy-pyridine-3-carboxamide    (Compound 1046),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3-fluorooxetan-3-yl)methoxy]pyridine-3-carboxamide    (Compound 1053),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-phenylpropoxy)pyridine-3-carboxamide    (Compound 1068),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(1-methylindol-7-yl)oxy-pyridine-3-carboxamide    (Compound 1071),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[[(1R,5S)-3-bicyclo[3.1.0]hexanyl]oxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1077),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(4-cyano-2,6-dimethyl-phenoxy)pyridine-3-carboxamide    (Compound 1089),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(4-fluoro-2-methyl-phenoxy)pyridine-3-carboxamide    (Compound 1104),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylcyclohexoxy)pyridine-3-carboxamide    (Compound 1108),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(cyclobutoxy)pyridine-3-carboxamide    (Compound 1154),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-cyclopropylethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1165),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R,2R,4S)-norbornan-2-yl]oxy-pyridine-3-carboxamide    (Compound 1216),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-norbornan-2-yloxy-pyridine-3-carboxamide    (Compound 1227),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cyclopropylmethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1229),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-cyclobutylethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1238),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,6-dimethylphenoxy)pyridine-3-carboxamide    (Compound 1243),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cycloheptoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1263),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(1-methyl-2-phenyl-ethoxy)pyridine-3-carboxamide    (Compound 1314),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2-methylphenoxy)pyridine-3-carboxamide    (Compound 1318),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-tetrahydropyran-4-yloxy-pyridine-3-carboxamide    (Compound 1324),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-norbornan-2-yloxy-pyridine-3-carboxamide    (Compound 1349),-   N-[(6-amino-2-pyridyl)sulfonyl]-7,7-dimethyl-2-(2,4,6-trimethylphenoxy)-6,8-dihydro-5H-quinoline-3-carboxamide    (Compound 665),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethylcyclopentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 416),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-tetrahydrofuran-3-yloxy-pyridine-3-carboxamide    (Compound 433),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methylcyclohexoxy)pyridine-3-carboxamide    (Compound 438),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 985),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1461),-   3-[[6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonyl]sulfamoyl]benzoic    acid (Compound 205),-   N-(3-aminophenyl)sulfonyl-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 231),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-phenethyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 268),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-benzyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1),-   N-(benzenesulfonyl)-2-(2,4,6-trimethylphenoxy)quinoline-3-carboxamide    (Compound 215),-   N-[(6-amino-2-pyridyl)sulfonyl]-8-methyl-2-(2,4,6-trimethylphenoxy)quinoline-3-carboxamide    (Compound 70),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)quinoline-3-carboxamide    (Compound 91),-   N-(3-aminophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)quinoline-3-carboxamide    (Compound 260),-   N-(4-pyridylsulfonyl)-2-(2,4,6-trimethylphenoxy)quinoline-3-carboxamide    (Compound 240),-   6-tert-butyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 214),-   6-tert-butyl-N-[(6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 262), and-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 15).

PREPARATION 7:6-tert-butyl-N-(2-hydroxyphenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 131)

6-tert-Butyl-N-(2-methoxyphenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 115) (99 mg, 0.21 mmol) was taken up in CH₂Cl₂ (10 mL). Themixture was cooled to −78° C. before BBr₃ (1.0 mL, 1M, 1.0 mmol) wasadded slowly. The mixture allowed to warm to room temperature overnight.The reaction mixture was diluted with saturated NaHCO₃ (10 mL) and wasextracted with ethyl acetate (2×5 mL). The organic layers were driedover sodium sulfate and concentrated. The residue was subjected topreparatory-HPLC (20-80% acetonitrile/water with 5 mM HCl) to give6-tert-butyl-N-(2-hydroxyphenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 131) (63 mg, 66%). ¹H NMR (400 MHz, DMSO) δ 11.66 (s, 1H),11.04 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.52 (s,1H), 7.16 (d, J=7.9 Hz, 1H), 7.02 (s, 2H), 6.93 (s, 2H), 2.26 (s, 3H),1.98 (s, 6H), 1.04 (s, 9H). ESI-MS m/z calc. 468.2, found 469.0 (M+1)⁺;Retention time: 2.16 min (3 min run).

The following compound can be synthesized using the procedures describedherein:6-tert-butyl-N-(3-hydroxyphenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 47) and

6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-hydroxyphenyl)sulfonyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 395).

PREPARATION 8: 6-tert-butyl-2-(1-phenylethyl)pyridine-3-carboxylic acidStep 1: 6-tert-butyl-2-(1-phenylethyl)pyridine-3-carbonitrile

A mixture of bromo(1-phenylethyl)zinc (4.1 mL of 0.5 M, 2.1 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (H)dichloromethane adduct (38 mg, 0.051 mmol) was stirred at roomtemperature under an atmosphere of nitrogen for 20 min.6-tert-Butyl-2-chloro-pyridine-3-carbonitrile (100 mg, 0.51 mmol) wasadded and the reaction mixture was heated at 150° C. for 10 min in amicrowave reactor. The mixture was concentrated and the residue wassubjected to silica gel column chromatography (0-20% ethylacetate/hexanes) to give6-tert-butyl-2-(1-phenylethyl)pyridine-3-carbonitrile (120 mg, 80.%).ESI-MS m/z calc. 264.2, found 265.4 (M+1)⁺; Retention time: 2.28 min (3min run).

Step 2: 6-tert-butyl-2-(1-phenylethyl)pyridine-3-carboxylic acid

A mixture of 6-tert-butyl-2-(1-phenylethyl)pyridine-3-carbonitrile (120mg, 0.45 mmol), KOH (1.1 mL of 4.0 M, 4.4 mmol) and EtOH (1.2 mL) washeated at 90° C. overnight. The mixture was concentrated and conc. HClwas added to the residue. The solids were collected and washed withwater. The solids were placed in a vacuum oven at 60° C. overnight togive a ˜1:1 mixture of6-tert-butyl-2-(1-phenylethyl)pyridine-3-carboxylic acid [ESI-MS m/zcalc. 283.2, found 284.3 (M+1)⁺; Retention time: 0.78 min (1 min run)]and 6-tert-butyl-2-(1-phenylethyl)pyridine-3-carboxamide [ESI-MS m/zcalc. 282.2, found 283.4 (M+1)⁺; Retention time: 0.69 min (1 min run)].

The following compound can be synthesized using the procedures describedherein:

-   6-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyridine-3-carboxylic    acid,-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(1-phenylethyl)pyridine-3-carboxamide    (Compound 271), and-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyridine-3-carboxamide    (Compound 346).

PREPARATION 9:6-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyridine-2-carboxylic acidStep 1: 5-bromo-2-tert-butylpyridine

tert-Butylmagnesium chloride (60 mL of a 1.0 N solution in THF, 60 mmol)was slowly added to a greenish suspension of CuCN (2.7 g, 30 mmol) inTI-IF (60 mL) cooled to −78° C. and the resulting gray mixture wasstirred at −78° C. for 1 h. A solution of 5-bromo-2-iodopyridine (4.3 g,15 mmol) in THF (10 mL) was then added. The reaction mixture was stirredat −78° C. for 1 h then at 0° C. for 3 h before being allowed to warm upgradually to room temperature overnight. Ammonium hydroxide (80 mL of20%) was added and the resulting mixture was filtered and washed withethyl acetate (100 mL). The filtrate was washed with brine (40 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to afford 5-bromo-2-tert-butylpyridine (2.2 g, 68%; contains20% heptanes) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 1.43 (s,9H), 7.23 (dd, J=8.5, 0.9 Hz, 1H), 7.71 (dd, J=8.5, 2.3 Hz, 1H), 8.60(d, J=2.3 Hz, 1H). [M+H]⁺=214.0.

Step 2: 5-bromo-2-tert-butylpyridine-N-oxide

3-Chlorobenzoperoxoic acid (4.40 g of 77% grade, 17.9 mmol) was added toa solution of 5-bromo-2-tert-butylpyridine (3.70 g, 13.8 mmol) indichloromehtane (45 mL). The reaction mixture was stirred at roomtemperature overnight. Ca(OH)₂ (4.1 g, 44 mmol) was added and theresulting mixture was then stirred at room temperature for 30 min beforebeing filtered through a pad of Celite. The filtrate was concentratedunder reduced pressure and the residue was purified by silica gelchromatography (0-50% ethyl acetate/heptanes) to afford5-bromo-2-tert-butylpyridine-N-oxide (2.7 g, 85%) as a white solid. ¹HNMR (300 MHz, CDCl₃) δ 1.48 (s, 9H), 7.19 (d, J=8.8 Hz, 1H), 7.31 (dd,J=8.8, 1.8 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H). [M+H⁺=230.0.

Step 3: 6-tert-butylpyridine-2-carbonitrile

Trimethylsilanecarbonitrile (8.8 mL, 70 mmol) and Et₃N (7.4 mL, 53 mmol)were added to a solution of 5-bromo-2-tert-butylpyridine-N-oxide (2.7 g,12 mmol) in acetonitrile (20 mL) at room temperature. The reactionmixture was then heated at 100° C. overnight. Additionaltrimethylsilanecarbonitrile (2.4 mL, 19 mmol) and Et₃N (2.1 mL, 15 mmol)were added and the reaction mixture was heated at reflux againovernight. Most of the acetonitrile was removed under reduced pressureand the residue was dissolved in ethyl acetate (100 mL). The organiclayer was washed with a saturated aqueous solution of NaHCO₃ (20 mL),brine (20 mL), dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-15%ethyl acetate/heptanes) to afford3-bromo-6-tert-butylpyridine-2-carbonitrile (2.6 g, 93%) as a colorlessoil. ¹H NMR (300 MHz, CDCl₃) δ 1.34 (s, 9H), 7.42 (d, J=8.5 Hz, 1H),7.89 (d, J=8.5 Hz, 1H). [M+H]⁺=238.9.

Step 4:6-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyridine-2-carbonitrile

Tetrakis(triphenylphosphine)palladium(O) (530 mg, 0.46 mmol) was addedto a solution of 3-bromo-6-tert-butylpyridine-2-carbonitrile (1.1 g, 4.6mmol) in THF (12 mL) in a sealed tube. The mixture was evacuated andbackfilled with nitrogen three times, then a stock solution of(2,4,6-trimethylphenyl)methylzinc bromide (9.2 mL of a 1.0 M solution inTHF, 9.2 mmol) was added at room temperature. The orange solution wasstirred at 60° C. overnight. The reaction mixture was quenched with 5%citric acid (20 mL) and the resulting mixture was extracted with ethylacetate (2×40 mL). The combined organic layers were washed with water(2×15 mL), brine (15 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (5-30% ethyl acetate/heptanes) to afford6-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyridine-2-carbonitrile(1.2 g, 89%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.32 (s, 9H),2.17 (s, 6H), 2.30 (s, 3H), 4.17 (s, 211), 6.91 (s, 2H), 6.97 (d, J=8.5Hz, 1H), 7.32 (d, J=8.5 Hz, 1H). [M+H]⁺=293.2.

Step 5:6-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyridine-2-carboxylic acid

6-tert-Butyl-3-[(2,4,6-trimethylphenyl)methyl]pyridine-2-carbonitrile(900. mg, 3.08 mmol) was dissolved in acetic acid (8 mL). ConcentratedHCl (8 mL) was added and the reaction mixture was stirred at 120° C. for3 d. Additional acetic acid (2 mL) and concentrated HCl (2 mL) wereadded and the reaction mixture was stirred at 120° C. for another 24 h.Most of the acetic acid was removed under reduced pressure and theresulting heterogeneous mixture was basified with 25% aqueous NaOH to apH of about 8-10. An aqueous solution of 5% citric acid (20 mL) was thenadded and the aqueous layer was extracted with methyl tert-butyl ether(2×50 mL). The combined organic layers were washed with water (2×20 mL),brine (20 mL), dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-50%ethyl acetate/heptanes) to afford6-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyridine-2-carboxylic acid(660 mg, 68.8%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.36 (s,9H), 2.12 (s, 6H), 2.31 (s, 3H), 4.57 (s, 2H), 6.91 (s, 2H), 7.07 (d,J=8.2 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 12.25 (br s, 1H). [M+H]⁺=312.2.

The following compounds can be synthesized using the proceduresdescribed herein:N-(benzenesulfonyl)-6-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyridine-2-carboxamide(Compound 22), andN-(3-aminophenyl)sulfonyl-6-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyridine-2-carboxamide(Compound 313).

PREPARATION 10:6-tert-butyl-3-(2,4,6-trimethylphenoxy)pyridine-2-carboxylic acid Step1: 6-tert-butyl-3-(2,4,6-trimethylphenoxy)pyridine-2-carbonitrile

A mixture of 3-bromo-6-tert-butylpyridine-2-carbonitrile (1.0 g, 4.2mmol), 2,4,6-trimethylphenol (0.57 g, 4.2 mmol) and Cs₂CO₃ (2.0 g, 6.3mmol) in DMSO (8 mL) was heated at 100° C. overnight. Once cooled toroom temperature, ethyl acetate (70 mL) was added and the organic layerwas washed with water (2×20 mL), brine (20 mL), dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography, (0-30% ethyl acetate/heptanes toafford 6-tert-butyl-3-(2,4,6-trimethylphenoxy)pyridine-2-carbonitrile(1.0 g, 81%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.33 (s, 9H),2.08 (s, 6H), 2.30 (s, 3H), 6.73 (d, J=9.1 Hz, 1H), 6.92 (s, 2H), 7.32(d, J=8.8 Hz, 1H). [M+H]⁺=295.1.

Step 2: 6-tert-butyl-3-(2,4,6-trimethylphenoxy)pyridine-2-carboxylicacid

6-tert-Butyl-3-(2,4,6-trimethylphenoxy)pyridine-2-carbonitrile (700 mg,2.38 mmol) was dissolved in acetic acid (9 mL). Concentrated HCl (9 mL)was added and the reaction mixture was heated at 120° C. for 2 d. Oncecooled to room temperature, the reaction mixture was concentrated todryness under reduced pressure. The residue was suspended in water (20mL) and 2N NaOH (3 mL) was added to provide a clear aqueous solution.The aqueous layer was washed with methyl tert-butyl ether (2×10 mL),acidified by the addition of 5% citric acid (20 mL) and the resultingmixture was extracted with ethyl acetate (2×50 mL). The combined organiclayers were washed with water (2×20 mL), brine (20 mL), dried overMgSO₄, filtered and concentrated under reduced pressure. The residue wastriturated with heptanes (10 mL) at 0° C. to afford6-tert-butyl-3-(2,4,6-trimethylphenoxy)pyridine-2-carboxylic acid (574mg, 77%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.37 (s, 9H),2.08 (s, 6H), 2.30 (s, 3H), 6.89-6.92 (m, 3H), 7.42 (d, J=8.9 Hz, 1H),11.68 (br s, 1H). [M+H]⁺=314.2.

The following compounds can be synthesized using the proceduresdescribed herein:N-(3-aminophenyl)sulfonyl-6-tert-butyl-3-(2,4,6-trimethylphenoxy)pyridine-2-carboxamide(Compound 106) andN-(benzenesulfonyl)-6-tert-butyl-3-(2,4,6-trimethylphenoxy)pyridine-2-carboxamide(Compound 350).

PREPARATION 11:N-(3-aminophenyl)sulfonyl-5-cyano-69methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 124) Step 1: ethyl5-cyano-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate

Ethyl 2-chloro-5-cyano-6-methyl-pyridine-3-carboxylate (518 mg, 2.31mmol), 2,4,6-trimethylphenol (377 mg, 2.77 mmol), and cesium carbonate(1.50 g, 4.61 mmol) were combined in N,N-dimethylformamide (5 mL) andheated at 90° C. for 1 h. The reaction mixture was cooled andpartitioned between ethyl acetate and 1N HCl. The organics wereseparated, washed with brine, dried over sodium sulfate and evaporatedto give ethyl5-cyano-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate.ESI-MS m/z calc. 324.2, found 325.2 (M+1)⁺; Retention time: 0.77 min (1min run).

Step 2: 5-cyano-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylicacid

Crude ethyl5-cyano-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate wasdissolved in methanol (12 mL) before NaOH (12 mL of 1.0 M, 12 mmol) wasadded. The mixture was heated at 70° C. for 3 h. The mixture was cooledand made acidic by the addition of 1 N HCl. The resulting precipitatewas collected by filtration. The solid was further dried to give5-cyano-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid(500 mg, 73% for 2 steps). ESI-MS m/z calc. 296.1, found 297.4 (M+1)⁺;Retention time: 0.63 min (1 min run).

Step 3:5-cyano-6-methyl-N-(3-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbaxamide

5-Cyano-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid(65 mg, 0.22 mmol), [(3-nitrophenyl)sulfonylamino]sodium (98 mg, 0.44mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (170 mg, 0.44 mmol) andN,N-dimethylformamide (1 mL) were combined and the mixture was stirredat room temperature for 1 h. The reaction mixture was diluted with water(1 mL) and was extracted with ethyl acetate (2×5 mL). The organic layerswere dried over sodium sulfate, filtered and concentrated. The residuewas subjected to preparatory-HPLC (20-80% acetonitrile/water with 5 mMHCl) to give5-cyano-6-methyl-N-(3-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide.ESI-MS m/z calc. 480.1, found 481.5 (M₊1)⁺; Retention time: 0.73 min (1min run).

Step 4:N-(3-aminophenyl)sulfonyl-5-cyano-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 124)

5-Cyano-6-methyl-N-(3-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(from step 3) was dissolved in methanol (10 mL) before 10% Pd/C (12 mg,0.011 mmol) was added. The mixture was stirred under a balloon ofhydrogen at room temperature for 2 h. The mixture was filtered andconcentrated. The residue was subjected to preparatory-HPLC (25-75%acetonitrile/water with 5 mM HCl) to giveN-(3-aminophenyl)sulfonyl-5-cyano-6-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 124) (15 mg, 15% for 2 steps). ESI-MS m/z calc. 450.1, found451.0 (M+1)⁺; Retention time: 1.68 min (3 min run).

PREPARATION 12:N-(2-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 322) Step 1:6-tert-butyl-N-(2-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

6-tert-Butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (50.mg, 0.16 mmol), 2-nitrobenzenesulfonamide (32 mg, 0.16 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (91 mg, 0.24 mmol), ethyldiisopropylamine(56 μL, 0.32 mmol) and NMP (1 mL) were combined. The mixture was heatedat 75° C. for 16 h before it was cooled to room temperature. Thereaction mixture was diluted with water (1 mL) and extracted with ethylacetate (2×5 mL). The combined organic layers were dried over sodiumsulfate, filtered and concentrated. The residue was subjected topreparatory-HPLC (30-90% acetonitrile/water with 5 mM HCl) to give6-tert-butyl-N-(2-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide.ESI-MS m/z calc. 497.2, found 498.4 (M+1)⁺; Retention time: 0.89 min (1min run).

Step 2:N-(2-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 322)

6-tert-Butyl-N-(2-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(23 mg, 0.046 mmol) was dissolved in EtOH (5 mL) before 10% Pd/C (2 mg,0.02 mmol) was added. The mixture was stirred under a balloon ofhydrogen at room temperature for 2 h. The mixture was filtered and thefiltrate was concentrated. The residue was subjected to preparatory-HPLC(20-80% acetonitrile/water with 5 mM HCl) to giveN-(2-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 322) (4.8 mg, 33%). ¹H NMR (400 MHz, DMSO) δ 8.06 (s, 1H),7.74 (s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.99 (s, 2H), 6.87 (s, 1H),6.72 (s, 1H), 2.34 (s, 3H), 2.04 (s, 6H), 1.33 (s, 2H), 1.13 (s, 9H).ESI-MS m/z calc. 467.2, found 468.0 (M+1)⁺; Retention time: 2.25 mM (3min run).

The following compounds can be synthesized using the proceduresdescribed herein:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2,6-dimethylphenoxy)pyridine-3-carboxamide(Compound 286),N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-cyclohexyl-pyridine-3-carboxamide(Compound 537),N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 294) andN-(3-amino-1-methyl-pyrazol-4-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 41).

PREPARATION 13:6-tert-butyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 51)

6-tert-butyl-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 191) (45 mg, 0.093 mmol) was dissolved in dioxane (1 mL)before aq HCl (0.5 mL of 4.0 M, 2.0 mmol) was added. The reactionmixture was heated at 90° C. for 1 h before it was cooled andconcentrated. The residue was subjected to preparatory-HPLC (20-80%acetonitrile/water with 5 μM HCl) to give6-tert-butyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 51) (19 mg, 20.%). NMR (400 MHz, DMSO) δ 12.57 (s, 1H), 11.83(s, 1H), 8.27 (dd, J=7.3, 2.1 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.83 (d,J=6.3 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 6.93 (s, 2H), 6.46 (t, J=6.8 Hz,1H), 2.27 (s, 3H), 1.99 (s, 6H), 1.05 (s, 9H). ESI-MS m/z calc. 469.2,found 470.3 (M+1)⁺; Retention time: 1.95 min (3 min run).

The following compound can be synthesized using the procedures describedherein:

-   6-tert-butyl-2-(2,4-dimethylphenoxy)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 55),-   7,7-dimethyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)-6,8-dihydro-5H-quinoline-3-carboxamide    (Compound 1199),-   2-(2,4-dimethylphenoxy)-8,8-dimethyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 634),-   8,8-dimethyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 899),-   6-(1-methylcyclopropyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1226),-   6-tert-butyl-N-[(4-methyl-2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1311),-   6-(4-ethoxy-3-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 901),-   6-(4-methylcyclohexyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 743),-   6-(4,4-dimethylcyclohexyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1091),-   6-(4,4-difluorocyclohexyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1329), and-   6-cyclohexyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1357).

PREPARATION 14: 6-Fluoropyridine-2-sulfonamide Step 1:2-(Benzylthio)-6-fluoropyridine

To a solution of BnSH (18.1 g, 146 mmol) in THF (1.12 L) was added 60%NaH (6.60 g, 165 mmol) portionwise over 10 minutes. The reaction mixturewas stirred at room temperature for 15 minutes after which time asolution of 2,6-difluoropyridine (13.7 mL, 150. mmol) in THF (100 mL)was added dropwise over 10 minutes. The resulting clear solution wasstirred at room temperature for 2 h. The reaction mixture was quenchedwith H₂O (250 mL) and the resultant mixture was extracted with Et₂O (800mL). The organic layer was washed with H₂O (400 mL) and brine (250 mL),dried over Na₂SO₄ and concentrated to dryness. The residue was purifiedby silica gel column chromatography (100% hexanes followed by a gradientof 1-10% ethyl acetate in hexanes) to give2-(benzylthio)-6-fluoropyridine (32.0 g, 100%). NMR (CDCl₃, 250 MHz) δ7.56 (q, J=8.0 Hz, 1H), 7.43-7.40 (m, 2H), 7.39-7.21 (m, 3H), 7.03 (dd,J=7.5, 2.3 Hz, 1H), 6.60 (dd, J=7.8, 2.5 Hz, 1H), 4.41 (s, 2H).

Step 2: 6-Fluoropyridine-2-sulfonyl chloride

2-(Benzylthio)-6-fluoropyridine (32.0 g, 146 mmol) was dissolved inCHCl₃ (500 mL) and H₂O (400 mL) was added. Chlorine was slowly bubbledthrough the reaction mixture for 2 h. (Note: a 30% aq. NaOH trap (1-1.5L) was used, followed by a sat. aq. Na₂S₂O₃ (1-1.5 L) trap to neutralizethe excess Cl₂). The reaction mixture became warm during the additionand a yellow suspension formed. The reaction was carefully quenched(exothermic and foaming) with a solution of Na₂S₂O₅ (200 g) in H₂O (450mL). The layers were separated and the aqueous layer was extracted oncewith CHCl₃ (200 mL). The organic layers were combined and washed withH₂O (300 mL), dried over Na₂SO₄ and concentrated to dryness to affordimpure 6-fluoropyridine-2-sulfonyl chloride as a brownish oil. Thismaterial was used as such in the next step.

Step 3: 6-Fluoropyridine-2-sulfonamide

Crude 6-fluoropyridine-2-sulfonyl chloride (from step 2) was dissolvedin CH₂Cl₂ (1 L) and the solution was cooled to −78° C. Ammonia wasbubbled through the solution for 25 min. The mixture was stirred for 1 hat room temperature and the precipitated product was removed byfiltration and washed with CH₂Cl₂ (2×). The filtrate and washings werecombined and concentrated to ˜50 mL and filtered; the solid was washedwith CH₂Cl₂/hexanes (50/50 mL) and dried to afford6-fluoropyridine-2-sulfonamide (12.0 g, 46% yield, purity ˜90%) as agrey solid. ¹H NMR (DMSO, 250 MHz) δ 8.27 (q, J=8.0 Hz, 1H), 7.88 (dd,J=7.5, 2.1 Hz, 1H), 7.66 (s, 2H), 7.48 (dd, J=8.0, 2.4 Hz, 1H).

PREPARATION 15:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 1255) Step 1:6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid

To a solution of 2,4,6-trimethylphenol (13.6 g, 100 mmol) inN,N-dimethylformamide (300 mL) at 0-5° C., was carefully added NaH solid(60% in mineral oil, 8.80 g, 220 mmol). After the resultant suspensionwas stirred at the same temperature for 15 min, solid2,6-dichloro-nicotinic acid (19.2 g, 100 mmol) was added. The reactionmixture was stirred at room temperature for 20 min and then at 80° C.overnight. The mixture was cooled to room temperature before it waspoured into a cold NaHSO₄ solution (24.0 g in 200 mL water). Theresultant suspension was stirred at room temperature for 30 min. Theprecipitate was collected by filtration, washed with water, followed byEt₂O/hexanes (200/500 mL), and dried at 40° C. under vacuum to give6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid as abrownish solid (19.2 g, 66%). ¹H NMR (400 MHz, DMSO) δ 13.38 (s, 1H),8.28 (d, J=7.9 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 6.94 (d, J=1.1 Hz, 2H),2.27 (s, 3H), 1.99 (s, 6H). ESI-MS m/z calc. 291.1, found 292.0 (M+1)⁺;Retention time: 2.34 min (3 min run).

Step 2:6-chloro-N4(6-fluoro-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

6-Chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (23.7 g,81.4 mmol) was added to a mixture ofN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (35.0 g, 92.1 6-fluoropyridine-2-sulfonamide(16.5 g, 93.8 mmol) and ethyldiisopropylamine (36 mL) inN,N-dimethylformamide (400 mL) at 5° C. The resulted mixture was stirredat room temperature overnight before it was quenched with 1 N HCl (150mL). The mixture was diluted with water (450 mL) and the resultantsolids were collected by filtration and washed with water (500 mL),methanol (200 mL) and Et₂O (400 mL). The solid was purified by silicagel column chromatography (0-4% methanol/CH₂Cl₂) to afford6-chloro-N-[(6-fluoro-2-pyridyl)sulfonyl[-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamideas a white solid (22.2 g, 60%). NMR (CDCl₃, 250 MHz) δ 8.36 (dd, J=15.7,7,5 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.58 (d,J=8.2 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 6.91 (s, 2H), 2.25 (s, 3H), 1.94(s, 6H).

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

6-Chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(12.0 g, 26.7 mmol) was mixed with NH₄OH (28-30%, 250 mL) and DMSO (200mL) in a 1 L pressure vessel at 0° C. The container was sealed andheated at 92° C. (oil bath) for 2 d, and at 85° C. for another 2 d.Solvents (water and DMSO) were removed and the residue was suspended ina mixture solvent of CH₂Cl₂/ethyl acetate/methanol (25/25/25 mL). Thesuspension was sonicated at room temperature for 15 min and wasfiltered. The solids were washed with CH₂Cl₂/ethyl acetate/methanol(10/10/10 mL) and dried to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamideas a white solid (6.8 g, 57%). ¹H NMR (CDCl₃, 250 MHz) δ 8.10 (d, J=7.8Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.21 (d, J=7.2Hz, 1H), 6.92 (s, 2H), 6.71 (d, J=8.5 Hz, 1H), 6.60 (br, s, 2H), 2.26(s, 3H), 1.98 (s, 6H).

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 1255)

A vial containing a mixture ofN-((6-aminopyridin-2-yl)sulfonyl)-6-chloro-2-(mesityloxy)-nicotinamide(30. mg, 0.067 mmol), 3-ethoxy-5-fluoro-benzeneboronic acid (25 mg, 0.13mmol), Pd(PPh₃)₄ (5.0 mg), K₃PO₄ (2.0 M, 0.13 mL) andN,N-dimethylformamide (0.6 mL) was flushed with nitrogen and sealed. Themixture was then heated at 80° C. overnight before it was cooled anddiluted with DMSO (0.3 mL). The mixture was subjected topreparatory-HPLC (30-90% acetonitrile/water with 5 μM HCl) to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 1255) (20 mg, 54%). ESI-MS m/z calc. 550.2, found 551.5(M+1)⁺; Retention time: 3.15 min (5 min run).

The following compounds can be synthesized using the proceduresdescribed herein:N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-tert-butylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 364),

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-cyclopropyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1050),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-dimethylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 399),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 639),-   N-[(6-amino-2-pyridyl)sulfonyl]-4-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)benzamide    (Compound 1549),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)-6-vinyl-pyridine-3-carboxamide    (Compound 430),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-hydroxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 505),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methyl-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 513),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-4-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 514),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methylindazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 451),-   N-[[6-(aminomethyl)-2-pyridyl]sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 871),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 457),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 463),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-isobutoxy-phenyl)-3-(2,4,6-trimethylphenoxy)pyridine-2-carboxamide    (Compound 1456),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-propylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 469),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4,4-dimethylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 538),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4,4-difluorocyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound783),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-ethyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 963),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-isopropyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1232),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-cyclopentyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1280),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-methoxypropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 791),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-pentyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 862),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxyethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 929),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-cyclohexyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1131),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(1-piperidyl)pyrimidin-5-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 475),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-methoxy-4-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 375),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-fluoro-2-methoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 387),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,4-difluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 439),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxy-3-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 450),-   N-[(6-amino-2-pyridyl)sulfonyl]-643-(morpholinomethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 465),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methoxy-3-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 477),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-2-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 396),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 436),-   6-(2-fluoro-4-methoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 374),-   6-(2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 391),-   6-(4-fluoro-2-methoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 405),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-6-(1-isobutylpyrazol-4-yl)pyridine-3-carboxamide    (Compound 381),-   6-(4-isopropoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 494),-   6-(1,3-benzodioxol-4-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 525),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 93),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-methylindol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 386),-   N-[(6-amino-2-pyridyl)sulfonyl]-643-(cyanomethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 388),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-methoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 413),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methoxypyrimidin-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 449),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 531),-   N-[(6-amino-2-pyridyl)sulfonyl]-643-fluoro-4-(isopropylcarbamoyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 543),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-ethoxy-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 599),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,6-dimethoxy-4-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 629),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(cyanomethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 638),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-3-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 661),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(m-tolyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 672),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 673),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 682),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(1-piperidylmethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 686),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 697),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-fluoro-2-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 700),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-difluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 725),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-fluoro-5-(hydroxymethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 727),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydropyran-4-yl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 748),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-hydroxy-3-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 768),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(dimethylamino)-3-pyridyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 787),-   6-[3-(aminomethyl)phenyl]-N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 801),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,5-difluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 803),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(morpholinomethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 810),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-dimethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 828),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluoro-2-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 830),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methyl-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1272),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methyl-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 730),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methyl-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1290),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxy-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 602),-   6-(6-methoxy-5-methyl-3-pyridyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1044),-   2-(2,4-dimethylphenoxy)-6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide    (Compound 610),-   2-(2,4-dimethylphenoxy)-6-(6-methoxy-5-methyl-3-pyridyl)-N-(1H-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide    (Compound 892),-   2-(2,4-dimethylphenoxy)-6-(3-fluoro-5-isopropoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide    (Compound 1213),-   2-(2,4-dimethylphenoxy)-6-(4-ethoxyphenyl)-N-(1H-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide    (Compound 813),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-propoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 535),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-2-hydroxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 866),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-6-(4-ethoxyphenyl)pyridine-3-carboxamide    (Compound 641),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-6-(3-fluoro-5-isopropoxy-phenyl)pyridine-3-carboxamide    (Compound 1150),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-6-(p-tolyl)pyridine-3-carboxamide    (Compound 1015),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1118),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1016),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(trifluoromethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 709), (Compound 709)-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 900),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 548),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-6-(6-methoxy-5-methyl-3-pyridyl)pyridine-3-carboxamide    (Compound 533),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-chloro-2-methoxy-4-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1284),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methoxy-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1034),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1133),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1138),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-fluoro-2-methoxy-4-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1277),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-4-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 860),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropylpyrazol-3-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1317),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-hydroxy-4-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 793),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-propoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 996),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxy-3-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1268),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1221),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-dihydro-2H-pyran-6-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 937),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-4-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1000),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(cyclopenten-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1330),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-2-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 897), (Compound 897)-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-4-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 875),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-isopropenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1211),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-chloro-2-methoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 993),-   6-(1-isobutylpyrazol-4-yl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 577),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1278),-   N-(1H-pyrazol-3-ylsulfonyl)-6-(2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1353),-   6-(3-ethoxy-5-fluoro-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 585),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1163),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1173),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1295),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 570),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluoro-2-hydroxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 622),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,6-dihydro-2H-pyran-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 976),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-difluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1325),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,4-dimethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 950),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 812),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-chloro-6-methoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1332),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,6-dimethoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 754),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 909),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 582),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(dimethylaminomethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 962),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-cyano-2-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1111),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-fluoro-6-methoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 612),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxypyridin-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1130),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methoxy-5-methyl-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 705),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methoxy-2-methyl-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1212),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 718),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,3-benzodioxol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 974),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,3-benzodioxol-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1207),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-benzyloxy-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1113),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-fluoro-2-hydroxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1409),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isopropylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 808),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1115),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-ethylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1312),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,5-dimethylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 584),-   6-phenyl-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 784),-   6-(4-methoxyphenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1033),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 939),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1H-indazol-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 856),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-cyanophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 886),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluoro-3-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 919),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-6-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 920),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-cyano-3-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 923),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,5-dimethylpyrazol-3-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 938),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-4-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 956),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1H-indol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 977),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,5-difluoro-4-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 984),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(p-tolyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1035),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-dihydrobenzofuran-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1084),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-methylindol-6-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1056),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methylpyrazol-3-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1057),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(o-tolyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1120),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(cyclopropylamino)pyrimidin-5-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1126),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(dimethylamino)pyrimidin-5-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1139),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-4-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1140),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-dimethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1146),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1147),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isobutylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1177),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1178),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1185),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-hydroxy-2-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1204),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,5-dimethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1225),-   6-[4-(aminomethyl)phenyl]-N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1228),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-difluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1244),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-hydroxy-4-methoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1251),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1255),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-pyrrolidin-1-ylpyrimidin-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1275),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-methylindazol-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1276),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methylindazol-6-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1299),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methoxy-5-methyl-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1320),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,6-dimethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1326),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isopentylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1336),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1337),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-hydroxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1344),-   N-[(6-amino-2-pyridyl)sulfonyl]-643-(hydroxymethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 786),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-hydroxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 908),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(hydroxymethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1183),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-dimethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 485),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,4-dimethoxypyrimidin-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 499),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 203),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 17),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 61),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,6-dimethylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 97),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 250),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-furyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 284),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(trifluoromethyl)-3-pyridyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 132),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-cyanophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 216),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 14),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(methoxymethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 66),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylphenoxy)-6-phenyl-pyridine-3-carboxamide    (Compound 340),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(methoxymethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 69),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropylpyrimidin-5-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 64),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methyl-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 513),-   N-[(6-amino-2-pyridyl)sulfonyl]-643-(hydroxymethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 786),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-hydroxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 908),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(hydroxymethyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1183),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-ethoxy-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 599),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(dimethylcarbamoyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-(methylcarbamoyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methylindazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 451),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-dimethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 828),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,5-dimethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1225),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isopentylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1336),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-propylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 469),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-hydroxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 505),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isobutylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1177),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-difluorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 725),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(2-cyanoethylcarbamoyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-4-(isopropylcarbamoyl)phenyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 543),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methyl-2-tetrahydropyran-4-yl-ethoxy)pyridine-3-carboxamide    (Compound 1361),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,1-dimethyl-2-phenyl-ethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1365),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-cyclopentylethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1374),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cyclohexylmethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1395),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylcyclobutoxy)pyridine-3-carboxamide    (Compound 406),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclobutylethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1418),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-phenethyloxy-pyridine-3-carboxamide    (Compound 1426),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(3-pyridyl)ethoxy]pyridine-3-carboxamide    (Compound 1434),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopentylethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1440),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cyclopropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1446),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cyclopentylmethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1450),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cyclopentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1451),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-difluorocyclobutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1458),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-tetrahydrofuran-3-yl]oxy-pyridine-3-carboxamide    (Compound 1464),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclohexylethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1465),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cyclohexoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1477),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-benzylcyclobutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1479),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(tetrahydrofuran-3-ylmethoxy)pyridine-3-carboxamide    (Compound 1499),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopropylcyclobutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1530),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyloxycyclobutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1559),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(tetrahydropyran-2-ylmethoxy)pyridine-3-carboxamide    (Compound 1570),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,4-dimethyl-3-pyridyl)oxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1574),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-tetrahydropyran-4-ylethoxy)pyridine-3-carboxamide    (Compound 1579),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cyclobutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1580),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-tetrahydrofuran-3-yl]oxy-pyridine-3-carboxamide    (Compound 1592),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-tetrahydrofuran-2-ylethoxy)pyridine-3-carboxamide    (Compound 1604),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-(4-pyridyl)ethoxy]pyridine-3-carboxamide    (compound 1605),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxycyclohexoxy)pyridine-3-carboxamide    (Compound 1622),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-(2-pyridyl)ethoxy]pyridine-3-carboxamide    (Compound 1625),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylcyclopentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1629),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-(2,2-dimethylcyclopropyl)propoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1639),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylcyclobutoxy)pyridine-3-carboxamide    (Compound 1644),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-(3-pyridyl)ethoxy]pyridine-3-carboxamide    (Compound 1654),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(tetrahydrofuran-2-ylmethoxy)pyridine-3-carboxamide    (Compound 1661),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide    (Compound 1668),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-tetrahydropyran-2-ylethoxy)pyridine-3-carboxamide    (Compound 1680),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopropylethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1685),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 8),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,6-dimethylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 97),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxy-3-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 161),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 164),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 196),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-2-fluoro-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 207),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 234),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 238),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 281),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 320),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(7-fluoro-1,3-benzodioxol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 345),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 351),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 172),-   6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 300),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 318), and-   6-(4-ethoxyphenyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 190).

PREPARATION 16:N-(3-aminophenyl)sulfonyl-5-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 1321) Step 1: methyl5-bromo-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate

2,4,6-Trimethylphenol (2.68 g, 19.7 mmol) and 60% NaH (870 mg, 22 mmol)were combined in an anhydrous mixture of N,N-dimethylformamide (24 mL)and THF (2.4 mL). The reaction mixture was stirred at room temperaturefor 15 minutes under an atmosphere of nitrogen. Methyl5-bromo-2-chloro-pyridine-3-carboxylate (4.93 g, 19.7 mmol) was addedand the reaction mixture was heated at 60° C. for 1 h. The reactionmixture was then allowed to cool to room temperature. The reactionmixture was diluted with water and was extracted with ethyl acetate. Theethyl acetate layer was washed three times with water and then wasconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography (0-50% ethyl acetate/hexanes) to yield methyl5-bromo-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (5.50 g, 73%)as a faint yellow solid. ESI-MS m/z calc. 349.0, found 350.3 (M₊1)⁺;Retention time: 2.09 min (3 min run).

Step 2: methyl 5-bromo-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate

Methyl 5-bromo-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (2.60 g,6.76 mmol) was combined in a mixture of methanol (12.95 mL) and water(17.27 mL) containing sodium hydroxide (810 mg, 20.3 mmol). Theresulting suspension was heated at 60° C. for 3 h. The reaction mixturewas cooled to room temperature and was made acidic with 6 M hydrochloricacid. The resulting precipitate was filtered, washed with water anddried in a vacuum oven at 60° C. overnight to yield5-bromo-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (2.24 g,98%) as a white solid. ESI-MS m/z calc. 335.0, found 338.2 (M+1)⁺;Retention time: 1.75 min (3 min run).

Step 3: methyl 5-bromo-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate

5-Bromo-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (89 mg,0.26 mmol), phenylboronic acid (39 mg, 0.32 mmol), Pd(PPh₃)₄ (31 mg,0.026 mmol), and K₂CO₃ (530 μL of 2.0 M, 1.1 mmol) were combined in DME(2.5 mL). The reaction mixture was briefly sparged with nitrogen,capped, and heated at 80° C. for 2 h. The reaction mixture was allowedto cool to room temperature and the layers were separated. The organiclayer was subjected to preparatory-HPLC (1-99% acetonitrile/water with5μM HCl) to give5-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (54 mg,61%) as a white solid. ESI-MS m/z calc. 333.1, found 334.4 (M+1)⁺;Retention time 0.72 min (1 min run).

Step 4:N-(3-nitrophenyl)sulfonyl-5-phenyl-2-(2,4,6-trimethylphenoxy)-pyridine-3-carboxamide

5-Phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (54 mg,0.16 mmol), (3-nitrophenyl)sulfonylazanide sodium (73 mg, 0.32 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (62 mg, 0.16 mmol) and N,N-dimethylformamide(1 mL) were combined. The reaction mixture was stirred at roomtemperature for 72 h. The crude mixture was subjected topreparatory-HPLC (1-99% acetonitrile/water with 5 μM HCl) to giveN-(3-nitrophenyl)sulfonyl-5-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(51 mg, 61%) as a white solid. ESI-MS m/z calc. 517.1, found 518.5(M+1)⁺; Retention time: 2.04 min (3 min run).

Step 5:N-(3-aminophenyl)sulfonyl-5-phenyl-2-(2,4,6-trimethylphenoxy)-pyridine-3-carboxamide

N-(3-nitrophenyl)sulfonyl-5-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(51 mg, 0.099 mmol) was suspended in acetic acid (2 mL) containing zinc(10 mg, 0.15 mmol). The reaction mixture was heated at 65° C. for 30min. The hot reaction mixture was filtered and then allowed to cool toroom temperature. The mixture was concentrated and the residue wassubjected to preparatory-HPLC (1-99% acetonitrile/water with 5 mM HCl)to giveN-(3-aminophenyl)sulfonyl-5-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 1321) (18 mg, 38%) as a white solid. ESI-MS m/z calc. 487.2,found 488.5 (M+1)⁺; Retention time: 2.74 min (3 min run).

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-propylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 429),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-isopropylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 865),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-tert-butylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 868),-   N-(3-aminophenyl)sulfonyl-6-tert-butyl-4-methoxy-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 959),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(o-tolyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 817), and-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-ethylphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 945).

PREPARATION 17:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carboxamide(Compound 193) Step 1:6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carbonitrile

A mixture of 6-tert-butyl-2-chloro-pyridine-3-carbonitrile (100. mg,0.514 mmol), N,2-dimethylaniline (76 μL, 0.62 mmol), KHMDS (1.2 mL of0.5 M, 0.62 mmol) and dioxane (1.5 mL) was heated at 100° C. for 20 min.The mixture was partitioned between ethyl acetate and 1N HCl. The layerswere separated and the aqueous layer was extracted with ethyl acetate(3×). The combined organics were washed with brine, dried over magnesiumsulfate, filtered and concentrated. The residue was subjected to silicagel column chromatography (0-25% ethyl acetate/hexanes) to give6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carbonitrile (40 mg,26%). ESI-MS m/z calc. 279.2, found 280.4 (M+I)⁺; Retention time: 2.28min (3 min run).

Step 2: 6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carboxamide

A mixture of 6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carbonitrile(40 mg, 0.14 mmol) and KOH (340 μL of 4.0 M, 1.4 mmol) in EtOH (1.2 mL)was heated at 90° C. overnight. The mixture was concentrated, acidifiedwith 2N HCl and the solids were collected to give an off-white solid.The solids were placed in a vacuum oven at 55° C. overnight to give6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carboxamide (40 mg, 30%)as an off-white solid. ESI-MS m/z calc. 297.2, found 298.4 (M+1)⁺;Retention time: 0.68 min (1 min run).

Step 3:6-tert-butyl-2-(N,2-dimethylanilino)-N-(3-nitrophenyl)sulfonyl-pyridine-3-carboxamide

Sodium hydride (16 mg, 60%, 0.40 mmol) was added to a mixture of6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carboxamide (40. mg, 0.13mmol) and N,N-dimethylformamide (1 mL). The mixture was allowed to stirfor 15 min before 3-nitrobenzenesulfonyl chloride (45 mg, 0.20 mmol) wasadded. The mixture was allowed to stir for 1H before adding two drops ofmethsanol. The mixture was filtered and subjected to preparatory-HPLC(10-99% acetonitrile/water with 0.05 mM HCl) to give6-tert-butyl-2-(N,2-dimethylanilino)-N-(3-nitrophenyl)sulfonyl-pyridine-3-carboxamide.ESI-MS m/z talc. 482.2, found 483.3 (M+1)⁺; Retention time: 0.82 min (1min run).

Step 4:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carboxamide(Compound 193)

Zinc (9.0 mg, 0.13 mmol) was added to a mixture of6-tert-butyl-2-(N,2-dimethylanilino)-N-(3-nitrophenyl)sulfonyl-pyridine-3-carboxamideand acetic acid (1 mL) at room temperature. The mixture was allowed tostir for 20 min before it was filtered and subjected to preparatory-HPLC(10-99% acetonitrile/water with 0.05 mMHCl) to giveN-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(N,2-dimethylanilino)pyridine-3-carboxamide(Compound 193) (1.2 mg, 2% for 2 steps). ESI-MS m/z talc. 452.2, found453.3 (M+1)^(÷); Retention time: 1.90 minutes (3 min run).

The following compound can be synthesized using the procedures describedherein:N-(3-aminophenyl)sulfonyl-6-tert-butyl-2-(N-methylanilino)pyridine-3-carboxamide(Compound 85).

PREPARATION 18:N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 110) Step 1: ethyl5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylate

To a mixture of ethyl 5-tert-butyl-4H-pyrazole-3-carboxylate (500. mg,2.55 mmol) and N,N-dimethylformamide (5 mL) was added2-(bromomethyl)-1,3,5-trimethyl-benzene (543 mg, 2.55 mmol) and. K₂CO₃(704 mg, 5.10 mmol). The reaction mixture was heated at 80° C.overnight. Additional 2-(bromomethyl)-1,3,5-trimethyl-benzene (200 mg,1.02 mmol) and K₂CO₃ (704 mg, 5.10 mmol) were added and the mixture washeated at 80° C. for another 18 h. The mixture was cooled to roomtemperature before water (20 mL) was added. The mixture was extractedwith ethyl acetate (2×50 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated. The residue wassubjected to silica gel column chromatography (0-50% ethylacetate/hexanes) to give ethyl5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylate(642 mg, 77%). ESI-MS m/z calc. 328.2, found 329.4 (M+1)⁺; Retentiontime: 0.99 min (1 min run).

Step 2:5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylic acid

Ethyl5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylate(5.00 g, 15.2 mmol) and NaOH (4.87 g, 122 mmol) were combined in a THF(20 mL) and water (20 mL). The mixture was heated at 60° C. for 3 h. Thereaction mixture was made acidic by the addition of 6 M HCl and wasextracted with ethyl acetate. The organics were washed with brine, driedover sodium sulfate and evaporated to give5-tert-butyl-2-[(2,4,6-trimethylphenyl)-methyl]pyrazole-3-carboxylicacid (4.38 g, 96%). ¹H NMR (400 MHz, DMSO) δ 13.23 (s, 1H), 6.83 (s,2H), 6.68 (s, 1H), 5.64 (s, 2H), 2.24 (s, 6H), 2.21 (s, 3H), 1.15 (s,9H). ESI-MS m/z calc. 300.2, found 301.4 (M+1)⁺; Retention time: 2.21min (3 min run).

Step 3:5-tert-butyl-N-(3-nitrophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide

5-tert-Butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylic acid(108 mg, 0.356 mmol), 3-nitrobenzenesulfonamide (109 mg, 0.539 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (137 mg, 0.356 mmol), and triethylamine (100μL, 0.719 mmol) were combined in N,N-dimethylformamide (2.3 mL) andheated at 60° C. for 16 h. The reaction mixture was filtered andsubjected to preparatory-HPLC (10-99% acetonitrile/water with 0.05mMHCl) to give5-tert-butyl-N-(3-nitrophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)-methyl]pyrazole-3-carboxamide(105 mg, 60.9%). ESI-MS m/z calc. 484.2, found 485.3 (M+1)⁺; Retentiontime: 2.27 min (3 min run).

4:N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]-pyrazole-3-carboxamide

5-tert-Butyl-N-(3-nitrophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]-pyrazole-3-carboxamide(105 mg, 0.217 mmol) was dissolved in methanol (9 mL) with Pd/C (38 mg,0.036 mmol) under a balloon of hydrogen and the mixture was stirred for30 min. The reaction mixture was filtered, evaporated, and the residuewas purified by LC/MS utilizing a gradient of 10-99% acetonitrile in 5mM aqueous HCl to yieldN-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 110) (72 mg, 44%). ¹H NMR (400 MHz, DMSO) δ 7.26 (t, J=7.9 Hz,1H), 7.21 (t, J=2.0 Hz, 1H), 7.12-7.06 (in, 1H), 7.01 (s, 1H), 6.89-6.83(m, 1H), 6.77 (s, 2H), 5.45 (s, 2H), 2.17 (s, 3H), 2.11 (s, 6H), 1.14(s, 9H). ESI-MS m/z calc. 454.2, found 455.4 (M+1)⁺; Retention time:2.06 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   3-(tert-butyl)-1-(1-mesitylethyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 201),-   N-(3-aminophenyl)sulfonyl-3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]pyrazole-4-carboxamide,-   3-(tert-butyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 35),-   3-(tert-butyl)-N-((3-(dimethylamino)phenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 270),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,4,6-trichlorobenzyl)-1H-pyrazole-5-carboxamide    (Compound 303),-   3-(tert-butyl)-1-(2,6-dimethylbenzyl)-N-((1-methyl-1H-indol-4-yl)sulfonyl)-1H-pyrazole-5-carboxamide    (Compound 210),-   N4(3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(4-(tert-butyl)-2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 156),-   3-(4-(difluoromethyl)phenyl)-1-(2,6-dimethylbenzyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 119),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-4-methoxy-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1305),-   N4(3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2-chloro-6-(trifluoromethyl)benzyl)-1H-pyrazole-5-carboxamide    (Compound 189),-   3-(tert-butyl)-N-P-(dimethylamino)-2-methylphenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 104),-   N-((3-amino-2-methylphenyl)sulfonyl)-3-(tert-butyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 123),-   3-(tert-butyl)-N-((1-methyl-1H-indol-7-yl)sulfonyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-pyrazole-5-carboxamide    (Compound 276),-   3-(tert-butyl)-N-(m-tolylsulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 80),-   N4(3-amino-4-fluorophenyl)sulfonyl)-3-(tert-butyl)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 150),-   3-(tert-butyl)-N-(quinolin-5-ylsulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 352),-   N4(3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,3,5,6-tetramethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 317),-   3-(tent-butyl)-1-(2,6-dimethylbenzyl)-N-(thiophen-2-ylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 77),-   3-(tert-butyl)-N-(phenylsulfonyl)-1-(2,4,6-trichlorobenzyl)-1H-pyrazole-5-carboxamide    (Compound 145),-   3-(tert-butyl)-1-(2,6-dimethylbenzyl)-N-((2-methoxy-3-methylphenyl)sulfonyl)-1H-pyrazole-5-carboxamide    (Compound 59),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[2-(2,4,6-trimethylphenyl)ethyl]pyrazole-3-carboxamide    (Compound 7),-   3-(tert-butyl)-N-(phenylsulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-1-(naphthalen-1-ylmethyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 328),-   3-(tert-butyl)-N-((3-(methylamino)phenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 249),-   3-(tert-butyl)-N-((1-(2-hydroxyethyl)-1H-indol-4-yl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 188),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-4-methyl-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 20),-   3-(tert-butyl)-1-(2,6-dimethylbenzyl)-N-((2-fluorophenyl)sulfonyl)-1H-pyrazole-5-carboxamide    (Compound 57),-   3-(tert-butyl)-N42-cyanophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 266),-   3-(tert-butyl)-N-((3-hydroxyphenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 84),-   3-(tert-butyl)-1-(2,6-dimethylbenzyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 257),-   N-((3-amino-4-methylphenyl)sulfonyl)-3-(tert-butyl)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 312),-   1-(3-(1H-pyrrol-1-yl)benzyl)-3-(tert-butyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 108),-   3-(tert-butyl)-1-(5-fluoro-2-(trifluoromethyl)benzyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 3),-   N-((3-acetylphenyl)sulfonyl)-3-(tert-butyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 332),-   N-((1H-indol-4-yl)sulfonyl)-3-(tert-butyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-pyrazole-5-carboxamide    (Compound 60),-   3-(tert-butyl)-N-((2,6-difluorophenyl)sulfonyl)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 170),-   N-((4-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 81),-   N4(3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-1H-pyrazole-5-carboxamide    (Compound 239),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(1-(o-tolyl)ethyl)-1H-pyrazole-5-carboxamide    (Compound 342),-   N-((6-aminopyridin-2-yl)sulfonyl)-3-(tert-butyl)-4-methyl-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 356),-   N-((2-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide,-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(1-cyclohexylethyl)-1H-pyrazole-5-carboxamide    (Compound 287),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(1-phenylpropyl)-1H-pyrazole-5-carboxamide    (Compound 165),-   3-(tert-butyl)-N-((4-hydroxyphenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 269),-   N-((3-aminophenyl)sulfonyl)-3-(1-methylcyclopropyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 158),-   3-(tert-butyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 98),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 185),-   N-((3-aminophenyl)sulfonyl)-3-isobutyl-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 167),-   3-(tert-butyl)-N-((2,3-dihydrobenzofuran-7-yl)sulfonyl)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 211),-   N-((6-aminopyridin-2-yl)sulfonyl)-3-(tert-butyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 173),-   3-(tert-butyl)-1-(2-methoxyphenethyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 157),-   N-((1H-indazol-4-yl)sulfonyl)-3-(tert-butyl)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 86),-   N-(benzenesulfonyl)-5-tert-butyl-2-[(1-methylindol-4-yl)methyl]pyrazole-3-carboxamide    (Compound 245),-   3-(tert-butyl)-N-((3-methoxypyridin-2-yl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide    (Compound 44),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(naphthalen-1-ylmethyl)-1H-pyrazole-5-carboxamide    (Compound 295),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-((1-methyl-1H-indol-7-yl)methyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-1-(2,6-dimethylbenzyl)-N-42-(methylamino)pyridin-4-yl)sulfonyl)-1H-pyrazole-5-carboxamide,-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(2-methoxyphenyl)sulfonyl-pyrazole-3-carboxamide    (Compound 1551),-   1-((1H-indol-7-yl)methyl)-N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1H-pyrazole-5-carboxamide,-   N-[(2-amino-3-pyridyl)sulfonyl]-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1106),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-((1-methyl    cyclohexyl)methyl)-1H-pyrazole-5-carboxamide,-   N-(4-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1653),-   3-(tert-butyl)-1-(4-(tert-butyl)-2,6-dimethylbenzyl)-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-N-((3-ethylphenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-N-((3-chlorophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-(1-phenylethyl)pyrazole-3-carboxamide    (Compound 799),-   N-((3-aminophenyl)sulfonyl)-3-isopropyl-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl-pyrazole-3-carboxamide    (Compound 1496),-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,4-dichlorobenzyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-N-((3-fluorophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-N-((2-methoxyphenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-N-((3-cyanophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   N-((4-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   N-((2-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-N-(pyridin-4-ylsulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   3-(tert-butyl)-N-((3-methoxyphenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide,-   N-((3-aminophenyl)sulfonyl)-3-(tert-butyl)-1-(2,4-dimethylbenzyl)-1H-pyrazole-5-carboxamide,-   5-tert-butyl-N-(1H-indol-4-ylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 180),-   3-(tert-butyl)-1-(5-methyl-2-(trifluoromethyl)benzyp-N-(phenylsulfonyl)-1H-pyrazole-5-carboxamide    (Compound 304),-   N-((3-aminophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-benzo[d]imidazole-2-carboxamide    (Compound 71),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(1-methylindol-4-yl)methyl]pyrazole-3-carboxamide    (Compound 927),-   5-tert-butyl-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 759),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(3-thienylsulfonyl)pyrazole-3-carboxamide    (Compound 603),-   N-(2-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 88),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(1H-indol-7-ylsulfonyl)pyrazole-3-carboxamide    (Compound 1358),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-(1H-indol-7-ylmethyl)pyrazole-3-carboxamide    (Compound 1256),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(1-methylindol-7-yl)methyl]pyrazole-3-carboxamide    (Compound 755),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-[[2-(methylamino)-4-pyridyl]sulfonyl]pyrazole-3-carboxamide    (Compound 821),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(1-methylcyclohexyl)methyl]pyrazole-3-carboxamide    (Compound 1152),-   N-(benzenesulfonyl)-5-tert-butyl-2-[(4-tert-butyl-2,6-dimethyl-phenyl)methyl]pyrazole-3-carboxamide    (Compound 443),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(1R)-1-phenylethyl]pyrazole-3-carboxamide    (Compound 540),-   N-[(2-amino-3-pyridyl)sulfonyl]-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide,-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(3-thienylsulfonyl)pyrazole-3-carboxamide    (Compound 603),-   5-tert-butyl-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 759),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(2-furylsulfonyl)pyrazole-3-carboxamide    (Compound 1468),-   N-[4-(aminomethyl)phenyl]sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1670),-   5-tert-butyl-N-(4-pyridylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1585),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4-dichlorophenyl)methyl]pyrazole-3-carboxamide    (Compound 797),-   5-tert-butyl-N-(3-ethylphenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 823),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-(1-phenylethyl)pyrazole-3-carboxamide,-   5-tert-butyl-N-(3-chlorophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 472),-   N-(2-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1167),-   N-(3-aminophenyl)sulfonyl-5-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 566),-   N-(1H-pyrazol-3-ylsulfonyl)-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 628),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 662),-   N-[(6-morpholino-2-pyridyl)sulfonyl]-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 669),-   N-[(6-(methylamino)-2-pyridyl]sulfonyl]-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 747),-   N-[[6-(2-hydroxyethylamino)-2-pyridyl]sulfonyl]-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 838),-   N-[(2-methoxy-3-pyridyl)sulfonyl)-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 876),-   N-[(6-methoxy-2-pyridyl)sulfonyl]-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 948),-   N-(benzenesulfonyl)-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 1039),-   N-[(6-amino-2-pyridyl)sulfonyl]-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 1055),-   N-(2-pyridylsulfonyl)-3-[(2,4,6-trimethylphenyl)methyl]-1,2,4,5-tetrahydro-3-benzazepine-4-carboxamide    (Compound 1093),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(1-methylindol-4-yl)methyl]pyrazole-3-carboxamide    (Compound 927), and-   N-(benzenesulfonyl)-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 45).

PREPARATION 19:5-tert-butyl-N-[3-(hydroxymethyl)phenyl]sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 39)

A solution of3-(tert-Butyl)-N-((3-formylphenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide(prepared following procedures described herein, 50 mg, 0.11 mmol) andanhydrous methanol (5 mL) was cooled to 0° C. The mixture was purgedwith nitrogen before adding sodium borohydride (7.6 mg, 0.20 mmol). Themixture was allowed to warm to room temperature and was stirredovernight. The reaction mixture was again cooled to 0° C. before addingadditional sodium borohydride (7.6 mg, 0.20 mmol). The mixture waswarmed to room temperature and was allowed to stir for 4 h. Solventswere removed and the crude residue was taken up in DMSO and subjected topreparatory-HPLC (10-99% acetonitrile/water with 0.05 mM HCl) to give5-tert-butyl-N-((3-(hydroxymethyl)phenyl]sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 39) (28 mg, 56%). ¹H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.99(s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.63 (dt, J=15.3, 7.7 Hz, 2H), 7.01 (s,1H), 6.75 (s, 2H), 5.42 (s, 2H), 4.63 (s, 2H), 2.16 (s, 3H), 2.07 (d,J=6.4 Hz, 6H), 1.14 (s, 9H). ESI-MS m/z talc. 469.2, found 470.0 (M+1)⁺;Retention time: 2.12 min (3 min run).

PREPARATION 20:N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(2-methoxyphenyl)pyrazole-3-carboxamide(Compound 347) Step 1: methylN-[(2,6-dimethylphenyl)methylamino]carbamate

2-(Chloromethyl)-1,3-dimethyl-benzene (25.0 g, 162 mmol), methylN-aminocarbamate (29.1 g, 323 mmol) and K₂CO₃ (33.5 g, 243 mmol) werecombined in N,N-dimethylformamide (150 mL) and heated at 80° C. for 2 h.The reaction mixture was concentrated and the crude material waspartitioned between ethyl acetate and water. The organics wereseparated, washed with brine and dried over sodium sulfate. The mixturewas filtered and the filtrate was concentrated. The residue wassubjected to silica gel column chromatography (0-60% ethylacetate/hexanes) to give methylN-[(2,6-dimethylphenyl)methylamino]carbamate (18.0 g, 53%). ESI-MS m/ztalc. 208.3, found 209.2 (M+1)⁺; Retention time: 0.41 min (1 min run).

Step 2: methyl2-[(2,6-dimethylphenyl)methyl]-5-hydroxy-pyrazole-3-carboxylate

Methyl N-[(2,6-dimethylphenyl)methylamino]carbamate (18.0 g, 86.4 mmol)was suspended in methanol (126 mL) and dimethyl but-2-ynedioate (10.6ML, 86.4 mmol) was added. The reaction mixture was stirred at reflux for2 h and was then cooled to room temperature. Sodium methoxide (20.5 mLof 25%w/v, 95.1 mmol) was added and the reaction mixture was againheated at reflux. After 1 h, the mixture was cooled to room temperatureand was added drop-wise to a flask containing 1M aq. HCl (300 mL) in anice water bath. The resulting precipitate was collected by vacuumfiltration. The solids were dissolved in CH₂Cl₂ and the excess water wasseparated and the organic layer was dried over sodium sulfate andevaporated to give methyl2-[(2,6-dimethylphenyl)methyl]-5-hydroxy-pyrazole-3-carboxylate (21.6 g,96%). ¹H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 7.10 (dd, J=8.4, 6.5 Hz,1H), 7.02 (d, J=7.5 Hz, 2H), 6.06 (s, 1H), 5.57 (s, 2H), 3.85 (s, 3H),2.24 (s, 6H). ESI-MS m/z calc. 260.1, found 261.4 (M+1)⁺; Retentiontime: 0.57 min (1 min run).

Step 3:2-[(2,6-dimethylphenyl)methyl]-5-(trifluoromethylsulfonyloxy)-pyrazole-3-carboxylate

Methyl 2-[(2,6-dimethylphenyl)methyl]-5-hydroxy-pyrazole-3-carboxylate(8.40 g, 32.3 mmol) and pyridine (3.13 mL, 38.7 mmol) were combined intoluene (84.00 mL) and cooled in a salt water/ice bath. Triflicanhydride (5.98 mL, 35.5 mmol) was added drop-wise keeping thetemperature below 0° C. After the addition was complete, the reactionmixture was warmed to room temperature and stirred for 1 h. The reactionmixture was quenched with water (30 mL) and the layers were separated.The aqueous layer was extracted with toluene (1×40 mL). The organicswere combined and washed with water (40 mL), dried over sodium sulfate,filtered and evaporated to give methyl2-[(2,6-dimethylphenyl)methyl]-5-(trifluoromethylsulfonyloxy)-pyrazole-3-carboxylate(12.4 g, 98%) ESI-MS m/z calc. 392.1, found 393.2 (M+1)⁺; Retentiontime: 0.82 min (1 min run).

Step 4:2-[(2,6-dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate

A suspension of methyl2-[(2,6-dimethylphenyl)methyl]-5-(trifluoromethylsulfonyloxy)pyrazole-3-carboxylate(12.1 g, 30.7 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(8.59 g, 33.8 mmol) and KOAc (9.05 g, 92.2 mmol) in dioxane (240 mL) wasdegassed for 10 min.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethaneadduct (1.26 g, 1.54 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (852mg, 1.54 mmol) were added and the reaction was degassed for anadditional 10 min. The reaction mixture was heated at 100° C. for 4 h.The mixture was concentrated to ˜100 mL total volume and was dilutedwith toluene (250 mL) and water (100 mL). The mixture was filteredthrough a pad of Celite to remove small black particulates. The organicswere separated, washed with water (100 mL) and dried over sodiumsulfate. The organics were filtered through a plug of silica (100 g) andthe silica was washed with another 1 L of toluene. The toluene wasevaporated to give methyl2-[(2,6-dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate(10.6 g, 93%). ¹H NMR (400 MHz, Chloroform-d) δ 7.27 (s, 1H), 7.09 (dd,J=8.2, 6.7 Hz, 1H), 7.00 (d, J=7.4 Hz, 2H), 5.86 (s, 2H), 3.81 (s, 3H),2.25 (s, 6H), 1.32 (s, 12H).

Step 5:2-[(2,6-dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylicacid

Methyl2-[(2,6-dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate(7.00 g, 14.2 mmol) was dissolved in THF (53 mL) and NaOH (43 mL of 1.0M, 43 mmol). The reaction mixture was heated at 60° C. for 2 h and wasconcentrated. The resulting solid was partitioned between ethyl acetateand a 1 N HCl solution. The organics were separated, washed with brine,dried over sodium sulfate and evaporated to give2-[(2,6-dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylicacid (5.5 g, 98%). ¹H NMR (400 MHz, DMSO) δ 13.44 (s, 1H), 7.13 (dd,J=8.3, 6.6 Hz, 1H), 7.07-7.02 (m, 3H), 5.81 (s, 2H), 2.23 (s, 6H), 1.24(s, 12H). ESI-MS m/z calc. 356.2, found 275.4 (M+1)⁺; Retention time:0.42 min (1 min run). Note: found mass is [-pinacol+H].

Step 6:N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxamide

2-[(2,6-Dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylicacid (4.14 g, 11.6 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (4.42 g, 11.6 mmol) andethyldiisopropylamine (6.07 mL, 34.9 mmol) were combined in CH₂Cl₂ (116mL). Benzenesulfonamide (2.19 g, 13.9 mmol) was added and the reactionmixture was stirred for 16 h before it was diluted with CH₂Cl₂ andwashed with 1N HCl. The organics were further washed with brine, driedover sodium sulfate, filtered and evaporated. The crude material waspurified by silica gel chromatography (0-100% ethyl acetate/hexanes) togiveN-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxamide(4.14 g, 72%). ESI-MS m/z calc. 495.2, found 414.4 (M+1)⁺; Retentiontime: 0.68 min (1 min run). Note: found mass is minus the pinacol ester.

Step 7:N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(2-methoxyphenyl)pyrazole-3-carboxamide(Compound 347)

N-(Benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxamide(50 mg, 0.10 mmol), 1-bromo-2-methoxybenzene (19 mg, 0.10 mmol),dichloro[1,1’-bis(diphenylphosphino)ferrocene[palladium (II)dichloromethane adduct (4 mg, 0.005 mmol), and 2M aq. K₂CO₃ (0.20 mL,0.40 mmol) were combined in N,N-dimethylformamide (0.6 mL) and heated at70° C. for 2 h. The reaction mixture was cooled, filtered and subjectedto preparatory-HPLC (10-99% acetonitrile/water with 0.05 mMHCl) to giveN-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(2-methoxyphenyl)pyrazole-3-carboxamide(Compound 347). ESI-MS m/z calc. 475.2, found 476.3 (M+1)¹; Retentiontime: 2.08 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-[2-(trifluoromethoxy)phenyl]pyrazole-3-carboxamide    (Compound 149),-   N-(benzenesulfonyl)-5-(4-chloro-3-methoxy-phenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 37),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(3-isopropoxyphenyl)pyrazole-3-carboxamide    (Compound 133),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(3-(trifluoromethoxy)phenyl[pyrazole-3-carboxamide    (Compound 225),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-[4-(trifluoromethypphenyl]pyrazole-3-carboxamide    (Compound 316),-   N-(benzenesulfonyl)-5-[3-(difluoromethyl)phenyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 315),-   N-(benzenesulfonyl)-5-(2,4-dimethoxyphenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 135),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(1-methylindol-4-yl)pyrazole-3-carboxamide    (Compound 363),-   N-(3-aminophenyl)sulfonyl-5-(2,6-dimethylphenyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 209),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(m-tolyl)pyrazole-3-carboxamide    (Compound 202),-   N-(3-aminophenyl)sulfonyl-5-(2-fluoro-3-methyl-phenyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide,-   N-(3-aminophenyl)sulfonyl-5-phenyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 367),-   N-(benzenesulfonyl)-5-[3-(dimethylamino)phenyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 178),-   N-(benzenesulfonyl)-5-[4-(diethylamino)phenyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 162),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4-fluorophenyl)pyrazole-3-carboxamide    (Compound 333),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(3-methoxyphenyl)pyrazole-3-carboxamide    (Compound 176),-   N-(benzenesulfonyl)-5-(4-dimethylaminophenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 76),-   N-(benzenesulfonyl)-5-(2-cyanophenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 99),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(3-fluoro-4-methoxy-phenyl)pyrazole-3-carboxamide    (Compound 43),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4-methoxyphenyl)pyrazole-3-carboxamide    (Compound 49),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-[3-(trifluoromethyl)phenyl]pyrazole-3-carboxamide    (Compound 220),-   N-(benzenesulfonyl)-5-(3-chlorophenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 83),-   N-(benzenesulfonyl)-5-(2-chlorophenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 339),-   N-(benzenesulfonyl)-5-(2,5-dimethoxyphenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 100),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxamide    (Compound 159),-   ethyl    2-[4-[5-(benzenesulfonylcarbarnoyl)-1-[(2,6-dimethylphenyl)methyl]pyrazol-3-yl]phenyl]acetate    (Compound 21),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-thienyl]pyrazole-3-carboxamide    (Compound 151),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(2-ethoxyphenyl)pyrazole-3-carboxamide    (Compound 152),-   N-(3-aminophenyl)sulfonyl-5-(2-methoxy-3-methyl-phenyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 208),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(2-fluorophenyl)pyrazole-3-carboxamide    (Compound 109),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(2-isopropoxyphenyl)pyrazole-3-carboxamide    (Compound 277),-   N-(benzenesulfonyl)-5-(4-chlorophenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 28),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4-ethoxyphenyl)pyrazole-3-carboxamide    (Compound 29),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(3-ethoxyphenyl)pyrazole-3-carboxamide    (Compound 280),-   N-(3-aminophenyl)sulfonyl-5-(2-methoxyphenyl)-2-(1-phenylethyl)pyrazole-3-carboxamide    (Compound 40),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(5-fluoro-2-methoxy-phenyl)pyrazole-3-carboxamide,-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-[2-(trifluoromethypphenyl]pyrazole-3-carboxamide    (Compound 369),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(p-tolyl)pyrazole-3-carboxamide    (Compound 199),-   N-(benzenesulfonyl)-5-[2-(dimethylamino)phenyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 128),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(3-fluorophenyl)pyrazole-3-carboxamide    (Compound 166),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(1-methylindol-5-yl)pyrazole-3-carboxamide    (Compound 263),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-[6-(1-piperidyl)-3-pyridyl]pyrazole-3-carboxamide    (Compound 329),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4-fluoro-2-methoxy-phenyl)pyrazole-3-carboxamide    (Compound 155),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-[3-(morpholinomethyl)phenyl]pyrazole-3-carboxamide    (Compound 302),-   N-(3-aminophenyl)sulfonyl-5-(2-methoxy-3-pyridyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 122),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(3-thienyl)pyrazole-3-carboxamide    (Compound 357),-   N-(3-aminophenyl)sulfonyl-5-(4-methoxyphenyl)-2-(1-phenylethyl)pyrazole-3-carboxamide    (Compound 1024),-   3-[5-(benzenesulfonylcarbamoyl)-1-[(2,6-dimethylphenyl)methyl]pyrazol-3-yl]benzoic    acid (Compound 343),-   N-(benzenesulfonyl)-5-(3-tert-butoxyphenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 744),-   N-(benzenesulfonyl)-5-(4H-1,3-benzodioxin-7-yl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1621),-   N-(benzenesulfonyl)-5-[2-(dimethylamino)pyrimidin-5-yl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1678),-   N-(benzenesulfonyl)-5-(5-chloro-3-fluoro-2-methoxy-phenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide,-   N-(benzenesulfonyl)-5-(5-chloro-3-fluoro-2-methoxy-phenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 379),-   N-(benzenesulfonyl)-5-(3-tert-butoxyphenyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 744),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4-isopropoxyphenyl)pyrazole-3-carboxamide    (Compound 1478),-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(4-oxochromen-3-yl)pyrazole-3-carboxamide    (Compound 1501),-   N-(3-aminophenyl)sulfonyl-5-(4-methoxyphenyl)-2-(1-phenylethyl)pyrazole-3-carboxamide    (Compound 1024)-   N-(3-aminophenyl)sulfonyl-5-(2-fluoro-3-methyl-phenyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 293), and-   N-(benzenesulfonyl)-2-[(2,6-dimethylphenyl)methyl]-5-(5-fluoro-2-methoxy-phenyl)pyrazole-3-carboxamide    (Compound 27).

PREPARATION 21:5-Benzyloxy-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylic acidStep 1: methyl3-(benzyloxy)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxylate

To a solution of methyl5-hydroxy-2-[(24,6-trimethylphenyl)methyl]pyrazole-3-carboxylate (250mg, 0.911 mmol) and K₂CO₃ (315 mg, 2.28 mmol) in N,N-dimethylformamide(5 mL) was added benzyl bromide (130 1.09 mmol) and the reaction mixturewas stirred at room temperature for 16 h. The mixture was concentratedand the resulting solids were partitioned between ethyl acetate andwater. The organics were separated, washed with brine, dried over sodiumsulfate and evaporated to give methyl3-(benzyloxy)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxylate. ESI-MSm/z calc. 364.2, found 365.4 (M+1)⁺; Retention time: 0.90 nun (1 minrun).

Step 2:5-benzyloxy-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carbaxylic acid

Methyl 3-(benzyloxy)-1-(2,6-dimethylbenzyl)-1H-pyrazole-5-carboxylate(from step 1) was dissolved in methanol (3 mL) before 1N NaOH (3 mL) wasadded. The reaction mixture was heated for 2 h at 60° C. andconcentrated. The crude mixture was partitioned between ethyl acetateand 1 N HCl. The organics were separated, washed with brine, dried oversodium sulfate, and evaporated to yield5-benzyloxy-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylic acid(295 mg, 92% for 2 steps) ESI-MS m/z calc. 350.2, found 351.4 (M+1)⁺;Retention time: 0.79 min (1 min run).

The following compound can be synthesized using the procedures describedherein:

-   3-(1-phenylethoxy)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxylic    acid,-   N-(3-aminophenyl)sulfonyl-5-benzyloxy-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 42), and-   N-(3-aminophenyl)sulfonyl-5-(1-phenylethoxy)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 278).

PREPARATION 22:N-(3-aminophenyl)sulfonyl-5-(3,3-dimethylbutyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 323) Step 1:5-[(E)-3,3-dimethylbut-1-enyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxylate

Methyl2-[(2,6-dimethylphenyl)methyl]-5-(trifluoromethylsulfonyloxy)pyrazole-3-carboxylate(500. mg, 1.27 mmol), [(E)-3,3-dimethylbut-1-enyl]boronic acid (196 mg,1.53 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane (52 mg, 0.064 mmol), and 2M K₂CO₃ (1.9 mL of 2.0 M, 3.8mmol) were combined in dioxane (10 mL) and irradiated in a microwavereactor for 30 min at 120° C. The reaction mixture was diluted withethyl acetate and was filtered through a pad of Celite. The filtrate waswashed with water, brine, dried over sodium sulfate and concentrated.The crude material was purified by silica gel column chromatography(0-60% ethyl acetate/hexanes) to give methyl5-[(E)-3,3-dimethylbut-1-enyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxylate(300. mg, 72%) ESI-MS m/z calc. 326.2, found 327.5 (M+1)⁺; Retentiontime: 0.94 min (1 min run).

Step 2:5-[(E)-3,3-dimethylbut-1-enyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxylate

Methyl5-[(E)-3,3-dimethylbut-1-enyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxylate(300. mg, 0.919 mmol) was dissolved in THF (3 mL) before adding NaOH(3.0 mL of 1.0 M, 3.0 mmol). The reaction mixture was heated for 2 h at60° C. and then concentrated. The resulting solid was partitionedbetween ethyl acetate and an aqueous solution of 1 N HCl. The organicswere separated, washed with brine, dried over sodium sulfate andconcentrated to give5-[(E)-3,3-dimethylbut-1-enyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxylicacid (198 mg, 69%). ESI-MS m/z calc. 312.2, found 313.5 (M+1)⁺;Retention time: 0.77 min (1 min run).

Step 3:(E)-3-(3,3-dimethylbut-1-en-1-yl)-N-((3-nitrophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide

5-[(E)-3,3-dimethylbut-1-enyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxylicacid (50. mg, 0.16 mmol), 3-nitrobenzenesulfonamide (32 mg, 0.16 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b[pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (61 mg, 0.16 mmol), andethyldiisopropylamine (84 μL, 0.48 mmol) were combined inN,N-dimethylformamide (1 mL) and stirred at room temperature for 16 h.The reaction mixture was filtered and subjected to preparatory-HPLC(10-99% acetonitrile/water with 0.05 mMHCl) to give(E)-3-(3,3-dimethylbut-1-en-1-yl)-N-((3-nitrophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide(23 mg, 29%). ESI-MS mz calc. 496.2, found 497.2⁺; Retention time: 0.85min (1 min run).

Step 4:N-(3-aminophenyl)sulfonyl-5-(3,3-dimethylbutyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 323)

A mixture of(E)-3-(3,3-dimethylbut-1-en-1-yl)-N-((3-nitrophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide(23 mg, 0.046 mmol), methanol (2 mL) and 10% Pd/C (17 mg, 0.016 mmol) atroom temperature was placed under a balloon of hydrogen The mixture wasstirred for 30 min before it was filtered. The filtrate was subjected topreparatory-HPLC (10-99% acetonitrile/water with 0.05 mM HCl) to giveN-(3-aminophenyl)sulfonyl-5-(3,3-dimethylbutyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 323) (4.0 mg, 17%). ESI-MS m/z calc. 468.2, found 469.0(M+1)⁺; Retention time: 2.11 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-(3-aminophenyl)sulfonyl-2-[(2,6-dimethylphenyl)methyl]-5-norbornan-2-yl-pyrazole-3-carboxamide    (Compound 370),-   N-[(6-amino-2-pyridyl)sulfonyl]-7-ethyl-2-[(2,4,6-trimethylphenyl)methyl]indazole-3-carboxamide    (Compound 1086), and-   N-(3-aminophenyl)sulfonyl-5-cyclopentyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 105).

PREPARATION 23:1-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-4-carboxylicacid Step 1:(E)-1-tert-butyl-2-[2-(2,4,6-trimethylphenyl)ethylidene]hydrazine

Acetic acid (0.2 mL) was added to a mixture of2-(2,4,6-trimethylphenyl)acetaldehyde (0.80 g, 4.9 mmol) andt-butylhydrazine hydrochloride (0.73 g, 4.9 mmol) in methanol (10 mL).The mixture was stirred at room temperature for 24 h. The reactionmixture was concentrated under reduced pressure and the residue wastreated with ether (20 mL) to give a precipitate which was collected byfiltration. The solid was suspended in ethyl acetate (150 mL), the pHadjusted to >7 by adding saturated NaHCO₃, the organic layer washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford(E)-1-tert-butyl-2-[2-(2,4,6-trimethylphenyl)ethylidene]hydrazine (0.80g, 70.%) as a yellow oil. ¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (s, 9H), 2.18(s, 3H), 2.23 (s, 6H), 3.68 (d, J=5.2 Hz, 2H), 6.85 (s, 2H), 8.24 (t,J=5.2 Hz, 1H), 11.39 (br s, 1H). ESI-MS m/z calc. 232.2, found 233.2(M+1)⁺; Retention time: 1.75 min (5 min run).

Step 2: ethyl1-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-4-carboxylate

A mixture of(E)-1-tert-butyl-2-[2-(2,4,6-trimethylphenyl)ethylidene]hydrazine (0.86g, 3.7 mmol) and ethylpropiolate (0.44 g, 4.5 mmol) in acetonitrile (3mL) and acetic acid (3 mL) was stirred at room temperature for 2 d. Thereaction mixture was concentrated under reduced pressure and the residuewas taken up with ethyl acetate (100 mL) before it was washed withsaturated NaHCO₃, brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel, eluting with 30% ethyl acetate in heptane to afford ethyl1-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-4-carboxylate(0.40 g, 33%) as a yellow solid. ESI-MS m/z calc. 328.2, found 329.2(M₊1)⁺; Retention time: 2.92 min (5 min run).

Step 4:1-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-4-carboxylicacid

A mixture of ethyl1-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-4-carboxylate(0.34 g, 1.0 mmol) and LiOHH₂O (0.22 g, 5.2 mmol) in methanol (4 mL) andwater (4 mL) was heated at reflux for 3 h. The reaction mixture wasconcentrated under reduced pressure and the pH of the aqueous layeradjusted to ˜3 with 5% citric acid. The aqueous layer was extracted withethyl acetate (150 mL), washed with brine, dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified by C₁₈column chromatography, eluting at 80% methanol in water to afford1-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-4-carboxylicacid (0.23 g, 74%) as a yellow solid. ESI-MS m/z calc. 300.2, found301.2 (M+1)⁺; Retention time: 2.41 min (5 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-(benzenesulfonyl)-1-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyrazole-4-carboxamide    (Compound 63) and-   N-(3-aminophenyl)sulfonyl-1-tert-butyl-3-[(2,4,6-trimethylphenyl)methyl]pyrazole-4-carboxamide    (Compound 324).

PREPARATION 24:1-tert-Butyl-4-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-3-carboxylicacid Step 1: 4-bromo-1-tert-butyl-1H-pyrazole-3-carboxylic acid

Concentrated sulfuric acid (0.24 mL, 4.3 mmol) was added to a suspensionof 4-bromo-1H-pyrazole-3-carboxylic acid (860 mg, 4.3 mmol) in t-BuOH(2.1 mL, 22 mmol). The reaction mixture was stirred at 100° C. for 2 h.Most of the solvent evaporated during the heating and a white solidremained in the flask. After cooling to room temperature, the pH wasadjusted to ˜4 by adding saturated aq. NaHCO₃. The aqueous layer wasextracted with ethyl acetate (2×40 mL). The combined organic layers werewashed with brine (20 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure to afford4-bromo-1-tert-butyl-1H-pyrazole-3-carboxylic acid (1.0 g, 89%) as awhite solid. ¹H NMR (300 MHz, DMSO) δ 1.52 (s, 9H), 8.23 (s, 1H), 12.92(br s, 1H).

Step 2: methyl 4-bromo-1-tert-butyl-1H-pyrazole-3-carboxylate

Potassium carbonate (1.1 g, 8.0 mmol) and iodomethane (0.3 mL, 4.8 mmol)were added to a solution of4-bromo-1-tert-butyl-1H-pyrazole-3-carboxylic acid (980 mg, 4.0 mmol) inN,N-dimethylformamide (6 mL). The reaction mixture was stirred at roomtemperature overnight. A 5% citric acid solution (20 mL) was added andthe aqueous layer was extracted with ethyl acetate (60 mL). The organiclayer was washed with water (2×15 mL), brine (15 mL), dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (0-30% ethylacetate/hexanes) to afford methyl4-bromo-1-tert-butyl-1H-pyrazole-3-carboxylate (1.1 g, quantitative) asa colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 1.57 (s, 9H), 3.94 (s, 3H),7.61 (s, 1H).

Step 3: methyl1-tert-butyl-4-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-3-carboxylate

Palladium acetate (45 mg, 0.20 mmol) and ^(t)Bu₃P.HBF₄ (120 mg, 0.40mmol) were added to a solution of methyl4-bromo-1-tert-butyl-1H-pyrazole-3-carboxylate (1.1 g, 4.2 mmol) intetrahydrofuran (10 mL) in a sealed tube. The reaction vessel wasevacuated and backfilled with nitrogen three times. A solution offreshly prepared (2,4,6-trimethylphenyl)methyl zinc bromide (8.0 mL of a1.0 M solution in THF, 8.0 mmol) was added at room temperature. Theorange-red solution was stirred at room temperature overnight. Theresulting black reaction mixture was quenched with 5% citric acidsolution (20 mL) and extracted with ethyl acetate (2×40 mL). Thecombined organic layers were washed with water (2×15 mL), brine (15 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (5 to 30% ethylacetate/hexanes) to give methyl1-tert-butyl-4-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-3-carboxylate(1.1 g, 87%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.47 (s, 9H),2.19 (s, 6H), 2.29 (s, 3H), 3.96 (s, 3H), 4.05 (s, 2H), 6.67 (s, 1H),6.87 (s, 2H).

Step 4:1-tert-butyl-4-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-3-carboxylicacid

A mixture of1-tert-butyl-4-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-3-carboxylate(1.00 g, 3.18 mmol), LiOH.H₂O (667 mg, 15.5 mmol), THF (10 mL) and water(10 mL) was stirred in a sealed tube at 60° C. for 4 h. The mixture wasacidified by adding 5% citric acid (30 mL) and was extracted with ethylacetate (2×30 mL). The combined organic layers were washed with water(2×15 mL), brine (15 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was triturated with a mixture ofmethyl tert-butyl ether (2 mL) and heptanes (2 mL) to afford1-tert-butyl-4-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazole-3-carboxylic(769 mg, 81%) as a white solid. ¹H NMR (300 MHz, DMSO) δ 1.41 (s, 9H),2.14 (s, 6H), 2.21 (s, 3H), 3.94 (s, 2H), 6.80 (s, 1H), 6.84 (s, 2H),12.60 (s, 1H).

The following compound can be synthesized using the procedures describedherein:N-(3-aminophenyl)sulfonyl-1-tert-butyl-4-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 366).

PREPARATION 25:1-tert-butyl-3-(2,4,6-trimethylphenoxy)-1H-pyrazole-4-carboxylic acidStep 1: 1-tert-butyl-1H-pyrazol-3-ol

tert-Butylhydrazine hydrochloride (3.03 g, 24.3 mmol) was added topyridine (30 mL) and the mixture was stirred for 1 h at roomtemperature. The mixture containing insoluble material was cooled to 5°C. then 3,3-diethoxypropanoyl chloride (3.27 g, 24.3 mmol) was addeddropwise. The mixture was then was heated at 80° C. for 48 h before itwas cooled to room temperature. The mixture was diluted with ethylacetate and the organic phase was washed with 5% aq. NaHCO₃ and brinebefore it was dried over anhydrous Na₂SO₄. The solids were filtered offand the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (5-50% ethylacetate/heptanes) to give a solid which was triturated in heptanes (1×10mL), filtered and dried to afford 1-tert-butyl-1H-pyrazol-3-ol (1.38 g,44%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.54 (s, 9H), 5.57(d, J=2.2 Hz, 1H), 7.24 (d, J=2.2 Hz, 1H), 12.11 (br. s, 1H). ESI-MS m/zcalc. 140.1, found 141.2 (M+1)⁺; Retention time: 1.12 min (5 min run).

Step 2: 4-bromo-1-tert-butyl-1H-pyrazol-3-ol

To 1-tert-butyl-1H-pyrazol-3-ol (1.30 g, 9.27 mmol) in dichloromethane(20 mL) was added NaHCO₃ (0.97 g, 11. mmol). The mixture was cooled to0° C. and a solution of bromine (1.56 g, 9.74 mmol) in dichloromethane(10 mL) was added dropwise. The mixture was stirred for 60 min at 0-10°C. before it was diluted with ethyl acetate. The organic phase waswashed with 5% NaHCO₃, 1% Na₂S₂O₃, 5% NaHCO₃, brine and dried overanhydrous Na₂SO₄. The solid was filtered off and the solvent was removedunder reduced pressure to afford 4-bromo-1-tert-butyl-1H-pyrazol-3-ol(1.87 g, 92% yield) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ1.53 (s, 9H), 7.31 (s, 1H), 11.58 (br. s, 1H). ESI-MS m/z calc. 218.0,found 219.1/221.1 (M+1)⁺; Retention time: 1.52 min (5 min run).

Step 3: 4-bromo-1-tert-butyl-3-(2,4,6-trimethylphenoxy)-1H-pyrazole

1-2-Dichloroethane (125 mL) was added to flame-dried 4 Å molecularsieves (4.81 g) and air was bubbled through the mixture for 15 minutes.4-Bromo-1-tert-butyl-1H-pyrazol-3-ol (1.75 g, 7.99 mmol) was addedfollowed by 2,4,6-trimethylphenylboronic acid (3.27 g, 20.0 mmol),pyridine (1.94 mL, 24.0 mmol) and copper (II) acetate (2.18 g, 12.0mmol). The reaction mixture was stirred under an air atmosphere for 72 hat room temperature before being diluted with ethyl acetate. The organicphase was washed with 10% NH₄OH, brine and dried over anhydrous Na₂SO₄.The solid was filtered off and the solvent was removed under reducedpressure. The residue was purified by silica gel column chromatography(5-75% dichloromethane/heptanes) to afford4-bromo-1-tert-butyl-3-(2,4,6-trimethylphenoxy)-1H-pyrazole (1.35 g,50%) as pale yellow solid. ¹H NMR (300 MHz, CDCl₃) δ1.41 (s, 9H), 2.15(s, 6H), 2.27 (s, 3H), 6.83 (s, 2H), 7.34 (s, 1H). ESI-MS m/z calc.336.1, found 337.1/339.1 (M₊1)⁺; Retention time: 2.54 min (5 min run).

Step 4: 1-tert-butyl-3-(2,4,6-trimethylphenoxy)-1H-pyrazole-4-carboxylicacid

To a solution of4-bromo-1-tert-butyl-3-(2,4,6-trimethylphenoxy)-1H-pyrazole (1.00 g,2.96 mmol) in THF (8 mL) cooled at −78° C. was added dropwise a 2.5 Msolution of n-buthyllithium in hexanes (1.36 mL, 3.41 mmol). The mixturewas stirred for 30 minutes at −78° C. and then CO₂ was bubbled throughthe solution for 45 min after which a chunk of dry ice was added to thereaction mixture. The reaction mixture was allowed to warm from −78° C.to −60° C. over 3 h. The reaction mixture was quenched by the additionof water (5 mL) at 0° C. before it was diluted with ethyl acetate (50mL). Citric acid (5%, aq.) was added under stirring to obtain pH of 4.The mixture was extracted with ethyl acetate. The combined organicextracts were washed with 5% aq. citric acid, 3% HCl, H₂O and brine anddried over anhydrous Na₂SO₄. The solid was filtered off and the solventwas removed under reduced pressure. The residue was triturated twice inheptanes/methyl tert-butyl ether (8 mL/0.5 mL) then purified by silicagel column chromatography 0-20% methanol/dichloromethane) to afford1-tert-butyl-3-(2,4,6-trimethylphenoxy)-1H-pyrazole-4-carboxylic acid(480 mg, 53% yield) as white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.42 (s,9H), 2.15 (s, 6H), 2.28 (s, 3H), 6.85 (s, 2H), 7.91 (s, 1H). ESI-MS m/zcalc. 302.2, found 303.2 (M+1)⁺; Retention time: 3.94 min (5 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-1-tert-butyl-3-(2,4,6-trimethylphenoxy)pyrazole-4-carboxamide    (Compound 256) and    N-(3-aminophenyl)sulfonyl-1-tert-butyl-3-(2,4,6-trimethylphenoxy)pyrazole-4-carboxamide    (Compound 325).

PREPARATION 26:N-(3-aminophenyl)sulfonyl-6-cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide(Compound 1082) Step 1: methyl6-cyano-1-(2,4,6-trimethylbenzyl)-1H-indole-2-carboxylate

Methyl 6-cyano-1H-indole-2-carboxylate (467 mg, 2.33 mmol) was dissolvedin N,N-dimethylformamide (25 mL) and cooled in an ice bath. NaH (60%,112 mg, 2.80 mmol) was added and the reaction mixture was stirred for 10min. 2-(Chloromethyl)-1,3,5-trimethyl-benzene (472 mg, 2.80 mmol) wasadded and the reaction mixture was allowed to warm to room temperatureand was stirred for 12 h. The reaction mixture was poured into ice waterand was made acidic with the addition of 1 N HCl. The resultingprecipitate was collected to give methyl6-cyano-1-(2,4,6-trimethylbenzyl)-1H-indole-2-carboxylate. ESI-MS m/zcalc. 332.2, found 333.2 (M+W; Retention time: 0.81 min (1 min run).

Step 2: 6-cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxylicacid

Methyl 6-cyano-1-(2,4,6-trimethylbenzyl)-1H-indole-2-carboxylate (fromstep 1) was stirred in a mixture of methanol (20 mL), THF (10 mL) andNaOH (9.34 mL of 1.0 M, 9.34 mmol) for 30 min. The reaction mixture wascooled in an ice bath and was acidified with 6 M HCl to a pH of 1. Themixture was extracted with ethyl acetate. The organics were washed withbrine, dried over sodium sulfate and evaporated to give6-cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxylic acid (740mg, 99% over two steps). ESI-MS m/z calc. 318.1, found 319.2 (M+1)⁺;Retention time: 0.68 min (1 min run).

Step 3:6-cyano-N-((3-nitrophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-indole-2-carboxamide

6-Cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxylic acid (35mg, 0.11 mmol), (3-nitrophenyl)sulfonylazanide sodium (37 mg, 0.16mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (42 mg, 0.11 mmol), and K₂CO₃ (46 mg, 0.33mmol) were combined in N,N-dimethylformamide (1 mL). The reactionmixture was heated at 60° C. for 2 h and was concentrated. The crudematerial was subjected to preparatory-HPLC (10-99% acetonitrile/waterwith 0.05 mM HCl) to give6-cyano-N-((3-nitrophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-indole-2-carboxamide.ESI-MS m/z calc. 502.1, found 503.2 (M+1)⁺; Retention time: 0.75 min (1min run).

Step 4:N-(3-aminophenyl)sulfonyl-6-cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide(Compound 1082)

6-Cyano-N-((3-nitrophenyl)sulfonyl)-1-(2,4,6-trimethylbenzyl)-1H-indole-2-carboxamide(from step 3) was mixed with methanol (2 mL) and 10% Pd/C (12 mg, 0.011mmol) under a balloon of hydrogen. After 1 h, the reaction mixture wasfiltered and the filtrate was concentrated. The residue was subjected topreparatory-HPLC (10-99% acetonitrile/water with 0.05 mMHCl) to giveN-(3-aminophenyl)sulfonyl-6-cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide(Compound 1082) (6.8 mg, 13% over two steps) ESI-MS m/z calc. 472.2,found 473.2 (M+1)⁺; Retention time: 1.71 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-(benzenesulfonyl)-6-chloro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 10),-   N-(benzenesulfonyl)-5-methoxy-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 241),-   N-(benzenesulfonyl)-4-chloro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 127),-   N-(benzenesulfonyl)-4-fluoro-1-(1-phenylethyl)indole-2-carboxamide    (Compound 160),-   N-(benzenesulfonyl)-6-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 12),-   N-(benzenesulfonyl)-5-chloro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 137),-   N-(benzenesulfonyl)-4-fluoro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 87),-   N-(benzenesulfonyl)-5-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 248),-   N-(benzenesulfonyl)-4-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 143),-   N-(benzenesulfonyl)-7-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 354),-   N-(benzenesulfonyl)-5-fluoro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 33),-   N-(3-aminophenyl)sulfonyl-4-chloro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 362),-   N-(3-aminophenyl)sulfonyl-4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 120),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-ethyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 179),-   N-(benzenesulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 264),-   N-(benzenesulfonyl)-1-[(2,6-dimethylphenyl)methyl]-4-methoxy-indole-2-carboxamide    (Compound 290),-   N-(benzenesulfonyl)-4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 348),-   N-(3-aminophenyl)sulfonyl-5-chloro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 344),-   N-(3-aminophenyl)sulfonyl-5-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 259),-   N-(3-aminophenyl)sulfonyl-6-chloro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 9),-   N-(3-aminophenyl)sulfonyl-6-fluoro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 142),-   N-(benzenesulfonyl)-6-fluoro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 212),-   N-(3-aminophenyl)sulfonyl-4-fluoro-1-(1-phenylethyl]indole-2-carboxamide    (Compound 186),-   N-(3-aminophenyl)sulfonyl-4-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 144),-   N-(3-aminophenyl)sulfonyl-1-[(2,6-dimethylphenyl)methyl]-4-methoxy-indole-2-carboxamide    (Compound 168),-   N-(3-aminophenyl)sulfonyl-4-fluoro-14(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 181),-   N-(3-methoxyphenyl)sulfonyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 335),-   N-(3-aminophenyl)sulfonyl-7-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 194),-   N-(3-aminophenyl)sulfonyl-5-methoxy-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 336),-   N-(2-methoxyphenyl)sulfonyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 183),-   N-[(6-methoxy-2-pyridyl)sulfonyl]-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 253),-   N-(3-aminophenyl)sulfonyl-5-fluoro-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 153),-   N-(3-aminophenyl)sulfonyl-6-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 62),-   N-(benzenesulfonyl)-3-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 232),-   N-(3-aminophenyl)sulfonyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 148),-   N-(2-hydroxyphenyl)sulfonyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 112),-   N-(benzenesulfonyl)-5,6-dimethoxy-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 198),-   N-(4-aminophenyl)sulfonyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 134),-   N-(benzenesulfonyl)-1-[(2,6-dimethylphenyl)methyl]indole-2-carboxamide    (Compound 2),-   N-(3-aminophenyl)sulfonyl-4-cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 306),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-5-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 267),-   4-fluoro-1-(1-phenylethyl)-N-(4-pyridylsulfonyl)indole-2-carboxamide    (Compound 192),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 18),-   N-(3-aminophenyl)sulfonyl-1-[(2,6-dimethylphenyl)methyl]indole-2-carboxamide    (Compound 331),-   N-(2-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 247),-   N-(2-cyanophenyl)sulfonyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 358),-   4-chloro-N-(4-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 82),-   6-methyl-N-(4-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 38),-   4-methoxy-N-(4-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 36),-   4-fluoro-N-(4-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 298),-   N-(4-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 227),-   5-methyl-N-(4-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 25),-   N-(3-aminophenyl)sulfonyl-3-methyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 118),-   N-(3-aminophenyl)sulfonyl-1-[(2,6-dimethylphenyl)methyl]-6-methoxy-indole-2-carboxamide    (Compound 116),-   N-[(3-methoxy-2-pyridyl)sulfonyl]-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 258),-   5-chloro-N-(4-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 65),-   6-chloro-N-(4-pyridylsulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 24),-   N-[(6-amino-2-pyridyl)sulfonyl]-1-[(4-cyano-2,6-dimethyl-phenyl)methyl]-5-methyl-indole-2-carboxamide    (Compound 67),-   N-[(4-amino-2-pyridyl)sulfonyl]-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 23),-   N-(3-aminophenyl)sulfonyl-5-cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 291),-   N-(3-aminophenyl)sulfonyl-5,6-dimethoxy-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 598),-   N-(3-aminophenyl)sulfonyl-6-cyano-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 1082),-   N-[(2-amino-4-pyridyl)sulfonyl]-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 627),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-isopropyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 404),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-methyl-1-(p-tolyl)indole-2-carboxamide    (Compound 653),-   N-(3-aminophenyl)sulfonyl-5,6-dimethoxy-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 598),-   N-(benzenesulfonyl)-1-[(2,6-dimethylphenyl)methyl]pyrrolo[2,3-b]pyridine-2-carboxamide    (Compound 1291),-   N-[(2-amino-4-pyridyl)sulfonyl]-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 627),-   (2R)—N-[(6-amino-2-pyridyl)sulfonyl]-1-[(2,4,6-trimethylphenyl)methyl]indoline-2-carboxamide    (Compound 462),-   (2R)—N-(benzenesulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]indoline-2-carboxamide    (Compound 918),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-propyl-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxamide    (Compound 1158),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-ethyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[2,3-b]pyridine-2-carboxamide    (Compound 816),-   N-(3-aminophenyl)sulfonyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[2,3-b]pyridine-2-carboxamide    (Compound 184), and-   N-(benzenesulfonyl)-1-[(2,6-dimethylphenyl)methyl]pyrrolo[2,3-b]pyridine-2-carboxamide    (Compound 1291).

PREPARATION 27:4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxylicacid Step 1: methyl4-chloro-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxylate

NaH (60%, 62 mg, 1.5 mmol) was added to a mixture of methyl4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (250. mg, 1.19 mmol)and N,N-dimethylformamide (5 mL) at 0° C. The mixture was allowed tostir for 15 min at 0° C. before a solution of2-(chloromethyl)-1,3,5-trimethyl-benzene (260. mg, 1.54 mmol) inN,N-dimethylformamide (1 mL) was added dropwise. The mixture was allowedto stir for 1H at room temperature, then 4 h at 60° C. The mixture waspartitioned between 1N HCl and ethyl acetate. The layers were separatedand the aqueous layer was extracted with ethyl acetate (3×). Thecombined organic layers were washed with brine (2×), dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theclear residue was subjected to silica gel column chromatography (0-20%ethyl acetate/hexanes) to give methyl4-chloro-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-d]pyridine-2-carboxylate(370 mg, 91%). ESI-MS m/z calc. 342.1, found 343.4 (M+1)⁺; Retentiontime: 2.09 min (3 min run).

Step 2: methyl4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxylate

A mixture of methyl4-chloro-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxylate(130. mg, 0.379 mmol) and NaOMe (7.6 mL of 0.50 M, 3.8 mmol) was heatedat 110° C. for 30 min in the microwave. The mixture was concentrated togive methyl4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxylate(56 mg, 15%) as a white solid. ESI-MS m/z calc. 338.2, found 339.4(M+1)⁺; Retention time: 0.64 min (1 min run).

Step 3:4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxylicacid

Lithium hydroxide (160 μL of 2.0 M, 0.32 mmol) was added to a mixture ofmethyl4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxylate(50. mg, 0.15 mmol) and EtOH (1 mL) at room temperature. The mixture wasallowed to stir at room temperature overnight. The mixture wasconcentrated and the residue was partitioned between 1N HCl and CH₂Cl₂.The layers were separated and the aqueous layer was extracted withCH₂Cl₂ (3×). The combined organics were washed with brine, dried overmagnesium sulfate, filtered and concentrated. The residue was taken upin N,N-dimethylformamide and subjected to preparatory-HPLC (10-99%acetonitrile/water with 0.05 niM HCl) to give4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxylicacid (39 mg, 81%) as a white solid. ESI-MS m/z calc. 324.2, found 325.4(M+1)⁺; Retention time: 0.52 min (1 min run).

The following compound can be synthesized using the procedures describedherein:N-(3-aminophenyl)sulfonyl-4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[3,2-c]pyridine-2-carboxamide(Compound 943)

-   and-   N-[(6-amino-2-pyridyl)sulfonyl]-4-methoxy-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[2,3-b]pyridine-2-carboxamide    (Compound 539)

PREPARATION 28:2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylic acidhydrochloride

A suspension of isoindoline-1-carboxylic acid (100 mg, 0.613 mmol) andKOH (103 mg, 1.84 mmol) in isopropanol (600 μL) was stirred until asolution was formed. 2-(Chloromethyl)-1,3,5-trimethyl-benzene (114 mg,0.674 mmol) was added and the reaction mixture was stirred for 3 h. Themixture was concentrated and the residue was subjected topreparatory-HPLC (10-99% acetonitrile/water with 0.05 mM HCl) to give24(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylic acidhydrochloride (99 mg, 49%). ¹H NMR (400 MHz, DMSO) δ 7.39-7.33 (m, 1H),7.34-7.25 (m, 3H), 6.87 (s, 2H), 4.97 (s, 1H), 4.34-3.94 (m, 4H), 2.40(s, 6H), 2.23 (s, 3H). ESI-MS m/z calc. 295.2, found 296.2 (M+1)⁺;Retention time: 0.43 min (1 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-(3-aminophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 90),-   N-(4-pyridylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 94),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 73),-   N-(3-methoxyphenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 16),-   N-(benzenesulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 6),-   N-(3-hydroxyphenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 254),-   N-[(6-methoxy-2-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 174),-   N-[(6-oxo-1H-pyridin-2-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 319),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 218),-   N-(2-methoxyphenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 79),-   N-(2-pyridylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 48),-   N-[(6-methoxy-3-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 200),-   N-(3-aminophenyl)sulfonyl-2-(1-phenylethyl)isoindoline-1-carboxamide    (Compound 187),-   N-(4-aminophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 121),-   N-[(4-amino-2-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 32),-   N-(2-aminophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 230),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-methyl-2-[(2,4,6-trimethylphenyl)methyl]-3,4-dihydro-1H-isoquinoline-3-carboxamide    (Compound 95),-   N-(3-aminophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]-3,4-dihydro-1H-isoquinoline-3-carboxamide    (Compound 213),-   N-[(6-amino--2-pyridyl)sulfonyl]-2-[1-(2,4,6-trimethylphenyl)ethyl]isoindoline-1-carboxamide    (Compound 1186),-   N-(benzenesulfonyl)-1-[(2,4,6-trimethylphenyl)methyl]-2,3,4,5-tetrahydro-1-benzazepine-2-carboxamide    (Compound 604),-   N-[(6-amino-2-pyridyl)sulfonyl]-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 895),-   N-[(3-hydroxy-2-pyridyl)sulfonyl]-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 377),-   N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-2-[(2-fluoro-6-methyl-phenyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1392),-   N-(3-amino-4-propyl-phenyl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1367),-   N-(3-amino-4-isopropyl-phenyl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1562),-   N-(3-amino-4-ethyl-phenyl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1584),-   N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-1-methyl-2-(o-tolylmethyl)isoindoline-1-carboxamide    (Compound 1408)-   4-ethoxy-N-indolin-5-ylsulfonyl-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1422)-   N-(2-aminophenyl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1457)-   N-(4-aminophenyl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1480)-   4-ethoxy-1-methyl-N-[[6-[(2,2,2-trifluoroacetyl)amino]-2-pyridyl]sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1616)-   N-[(6-acetamido-2-pyridyl)sulfonyl]-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1415)-   N-[(6-amino-3-pyridyl)sulfonyl]-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1413)-   4-ethoxy-N-(2-hydroxyphenyl)sulfonyl-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1509)-   4-ethoxy-N-(4-hydroxyphenyl)sulfonyl-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1453)-   4-ethoxy-1-methyl-N-(3-pyridylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1669)-   N-[(6-amino-5-chloro-2-pyridyl)sulfonyl]-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1596)-   4-ethoxy-N-(3-methoxyphenyl)sulfonyl-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1470)-   N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-2-[(3-fluoro-5-isobutoxy-phenyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1681)-   4-ethoxy-1-methyl-N-thiazol-5-ylsulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1606)-   4-ethoxy-N-(1H-indol-6-ylsulfonyl)-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1393)-   N-[[6-(difluoromethyl)-2-pyridyl]sulfonyl]-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1597)-   4-ethoxy-N-[(3-hydroxy-2-pyridyl)sulfonyl]-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1642) (Compound 377)-   4-ethoxy-1-methyl-N-thiazol-4-ylsulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1542)-   4-ethoxy-1-methyl-N-(4-pyridylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1449)-   4-ethoxy-N-(1H-indol-4-ylsulfonyl)-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1666)-   N-(2-acetamidothiazol-5-yl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1555)-   4-ethoxy-N-(3-fluoro-2-methoxy-phenyl)sulfonyl-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1403)-   4-ethoxy-1-methyl-N-(2-pyridylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1474)-   4-ethoxy-1-methyl-N-thiazol-2-ylsulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1546)-   4-ethoxy-N-(3-fluorophenyl)sulfonyl-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1425)-   N-[(2-amino-3-pyridyl)sulfonyl]-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1591)-   N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-2-[(6-isopropoxy-3-pyridyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1662)-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,6-dimethylphenyl)methyl]-4-ethoxy-1-methyl-isoindoline-1-carboxamide    (Compound 1498)-   2-[(2,6-dimethylphenyl)methyl]-4-ethoxy-N-[(6-fluoro-2-pyridyl)sulfonyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1676)-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(6-chloro-3-pyridyl)methyl]-4-ethoxy-1-methyl-isoindoline-1-carboxamide    (Compound 1565)-   N-(benzenesulfonyl)-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1539)-   N-(3-aminophenyl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1454)-   N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-2-[(4-isopropylphenyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1576)-   4-ethoxy-N-[(6-fluoro-2-pyridyl)sulfonyl]-2-[(4-isopropylphenyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1655)-   N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-2-[(4-fluorophenyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1433)-   4-ethoxy-2-[(4-fluorophenyl)methyl]-N-[(6-fluoro-2-pyridyl)sulfonyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1583)-   N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-2-[(3-fluoro-5-methoxy-phenyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1421)-   4-ethoxy-2-[(3-fluoro-5-methoxy-phenyl)methyl]-N-[(6-fluoro-2-pyridyl)sulfonyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1428)-   (1S)—N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1372) (Compound 1346)-   (1R)—N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1582) (Compound 1346)-   (1S)-4-ethoxy-1-methyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1541) (Compound 1237) (Compound 410)-   (1R)-4-ethoxy-1-methyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1476) (Compound 1237) (Compound 410)-   N-(3-amino-4-chloro-phenyl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1587)-   N-(3-amino-4-fluoro-phenyl)sulfonyl-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1394)-   N-(3-aminopyrazin-2-yl)sulfonyl-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 480),-   1-methyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1237),-   N-(3-aminophenyl)sulfonyl-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1273),-   N-(benzenesulfonyl)-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 873),-   1-methyl-N-(1H-pyrazol-5-ylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 378),-   N-[(6-amino-2-pyridyl)sulfonyl]-1-methyl-2-(o-tolylmethyl)isoindoline-1-carboxamide    (Compound 666),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 765),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,6-dimethylphenyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 790),-   N-[(3-methoxy-2-pyridyl)sulfonyl]-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 825),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,4-dimethylphenyl)methyl]-1-methyl-isoindoline-1-carboxamide    (Compound 1058),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-3,3-dimethyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1235),-   4-ethoxy-1-methyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1237) (Compound 410),-   N-[(6-amino-2-pyridyl)sulfonyl]-7-methoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1075),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-methoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 474),-   N-[(6-amino-2-pyridyl)sulfonyl]-4-methoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1161),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-methoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 406),-   4-ethoxy-N-[(2-methoxy-3-pyridyl)sulfonyl]-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 765) (Compound 648),-   N-[(6-amino-2-pyridyl)sulfonyl]-4-ethoxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1346),-   N-(3-amino-4-methyl-phenyl)sulfonyl-3,3-dimethyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 448),-   N-(5-amino-2-methyl-phenyl)sulfonyl-3,3-dimethyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 840),-   N-[(6-amino-2-pyridyl)sulfonyl]-7-hydroxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 394),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-hydroxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 885),-   N-[(6-amino-2-pyridyl)sulfonyl]-4-hydroxy-1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1338),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]-1,3,4,5-tetrahydro-2-benzazepine-3-carboxamide    (Compound 855),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]-1,3,4,5-tetrahydro-2-benzazepine-3-carboxamide    (Compound 1342),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]-1,3,4,5-tetrahydro-2-benzazepine-3-carboxamide    (Compound 690),-   3,3-dimethyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1085),-   N-[(6-amino-2-pyridyl)sulfonyl]-3,3-dimethyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 1101),-   N-(benzenesulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]-1,3,4,5-tetrahydro-2-benzazepine-1-carboxamide    (Compound 674),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]-1,3,4,5-tetrahydro-2-benzazepine-1-carboxamide    (Compound 696),-   N-(3-aminophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]-3,4-dihydro-1H-isoquinoline-1-carboxamide    (Compound 309), and-   (2S,4R)-N-[(6-amino-2-pyridyl)sulfonyl]-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide.

PREPARATION 29:4-isopropyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 103) Step 1: 2,6-dibromobenzaldehyde

To a solution of iPr₂NH (21.2 mL, 150 mmol) in THF (180 mL) at 0° C. wasslowly added n-BuLi (1.6 M, 94 mL, 150 mmol). The reaction mixture wasstirred at 0° C. for 30 min and then cooled to −78° C.1,3-Dibromobenzene (17.6 g, 74.6 mmol) in THF (80 mL) was slowly addedover 20 min. The mixture was stirred at −78° C. for 30 min andN,N-dimethylformamide (11.6 mL, 150 mmol) was added. The mixture wasstirred for 1 h, then treated with H₂SO₄ (2.5 M, 350 mL), and extractedwith ethyl acetate/Et₂O (50/50, 3×300 mL). The combined extract weredried over MgSO₄ and filtered. The filtrate was concentrated to give2,6-dibromobenzaldehyde (17.6 g, 89%). ¹H NMR (250 MHz, CDCl₃) δ 10.3(s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.23 (t, J=8.1 Hz, 1H).

Step 2: methyl (2,6-dibromobenzyl)glycinate

To a solution of glycine methyl ester hydrochloride (21.0 g, 167 mmol),2.6-dibromobenzaldehyde (16.9 g, 64.4 mmol) and triethylamine (21.0 mL,142 mmol) in dichloroethane (380 mL) were added acetic acid (8.40 mL,145 mmol) and NaBH(OAc)₃ (33.5 g, 158 mmol). The mixture was stirred atroom temperature under an argon atmosphere for 20 h. Additional glycinemethyl ester hydrochloride (8.10 g, 64.4 mmol), triethylamine (9.52 g,64.4 mmol), acetic acid (3.73 mL, 64.4 mmol) and NaBH(OAc)₃ (13.7 g,64.4 mmol) were added and the reaction mixture was stirred for another10 h. The reaction mixture was quenched by adding 1N NaOH, and theproduct was extracted with dichloromethane. The organic extracts werewashed with brine, dried over sodium sulfate, filtered, and the solventwas removed in vacuo. The residue was purified by a plug filtrationthrough a silica gel pad (0-50% ethyl acetate/hexanes to give methylmethyl (2,6-dibromobenzyl)glycinate (13.3 g, 62%) as an oil. ¹H NMR(CDCl₃, 250 MHz) δ 7.52 (d, J=8.0 Hz, 2H), 6.98 (t, J=8.0, 1H), 4.20 (s,2H), 3.70 (s, 3H), 3.50 (s, 2H).

Step 3: methyl N-(2,6-dibromobenzyl)-N-(2,4,6-trimethylbenzyl)glycinate

A mixture of methyl (2,6-dibromobenzyl)glycinate (13.3 g, 39.5 mmol),2,4,6-trimethylbenzyl bromide (7.32 g, 43.4 mmol), K₂CO₃ (12.0 g, 86.8mmol), and LiI (300 mg) in acetonitrile (300 mL) was stirred at 60° C.for 24 h. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (0-20% ethyl acetate/hexanes) to give methyl.N-(2,6-dibromobenzyl)-N-(2,4,6-trimethylbenzyl)glycinate (18.0 g, 97%)as an oil which solidified on standing. ¹H NMR (CDCl₃, 250 MHz) δ 7.54(d, J=7.8 Hz, 2H), 7.00 (t, J=8.0, 1H), 6.79 (s, 2H), 4.34 (s, 2H), 4.04(s, 2H), 3.71 (s, 3H), 3.50 (s, 2H), 2.23 (s, 3H), 2.18 (s, 6H).

Step 4: methyl4-bromo-2-(2,4,6-trimethylbenzyl)isoindoline-1-carboxylate

A mixture of methylN-(2,6-dibromobenzyl)-N-(2,4,6-trimethylbenzyl)glycinate (16.0 g, 34.1mmol), Cs₂CO₃ (33.3 g, 102 mmol) and Pd(PPh₃)₄ (2.0 g, 1.7 mmol) in THF(200 mL) was stirred at 110° C. in a sealed vessel for 60 h. Some THF(˜50 mL) was removed by flushing with N₂ before Cs₂CO₃ (6.5 g, 20 mmol)and Pd(PPh₃)₄ (400 mg, 0.34 mmol) were added. The reaction mixture wasstirred at 110° C. for 24 h. The mixture was poured into water and wasextracted with Et₂O. The organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The residue was purifiedby silica gel column chromatography (5-20% CH₂Cl₂/hexanes) to givemethyl 4-bromo-2-(2,4,6-trimethylbenzypisoindoline-1-carboxylate (2.9 g,22%). MS: 389 [M+1]⁺.

Step 5: 4-bromo-2-(2,4,6-trimethylbenzyl)isoindoline-1-carboxylic acidhydrochloride

Methyl 4-bromo-2-(2,4,6-trimethylbenzyl)isoindoline-1-carboxylate (2.9g, 7.4 mmol) was combined in a mixture of methanol (45 mL) and water (20mL) containing sodium hydroxide (900. mg, 22.5 mmol). The resultingsuspension was heated at 80° C. for 1 h. The reaction mixture wasconcentrated to remove the methanol. Water (50 mL) was added and themixture was extracted with Et₂O. The aqueous phase was adjusted to pH 2with 6N HCl and was then extracted with CH₂Cl₂. The extract was driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel column chromatography (0-5% methanol/CH₂Cl₂) and thensubjected to preparatory-HPLC (10-100% acetonitrile/water with 0.05 mMtrifluoroacetic acid) to give the desired product as the trifluoroaceticacid salt. The material was dissolved in methanol (30 mL) and wastreated with HCl (1M, 10 mL). The mixture was then concentrated todryness. The solid was suspended in CH₂Cl₂ (15 mL), sonicated for 10 minand filtered. The solid was washed with Et₂O and hexanes, and dried togive 4-bromo-2-(2,4,6-trimethylbenzyl)isoindoline-1-carboxylic acidhydrochloric acid (1.5 g, 49%). ¹H NMR (DMSO, 250 MHz) δ 7.65 (d, J=7.8Hz, 1H), 7.51 (d, J=7.8, 1H), 7.39 (m, 1H), 6.95 (s, 2H), 5.87 (s, 1H),4.68 (s, 2H), 4.52 (d, J=10.8 Hz, 1H), 4.30 (d, J=10.8 Hz, 1H), 2.46 (s,6H), 2.26 (s, 3H). MS: 375 [M+1]⁺.

Step 6:4-isopropenyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylicacid hydrochloride

4-Bromo-24(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylic acidhydrochloride (374 mg, 0.914 mmol),2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (269 mg, 1.60mmol) and cesium carbonate (652 mg, 2.00 mmol) in dioxane (9 mL) andwater (900 μL) was degassed with a stream of nitrogen for 1 min beforeadding dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (73 mg, 0.10 mmol). The reaction mixture wasdegassed with a stream of nitrogen for 1 min and the mixture was stirredat 120° C. for 2 h. The reaction mixture was filtered and subjected topreparatory-HPLC (10-99% acetonitrile/water with 0.05 mM HCl) to give4-isopropenyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylicacid hydrochloric acid (180 mg, 48%). ESI-MS m/z calc. 335.2, found336.2 (M+1)⁺; Retention time: 0.53 min (1 min run).

Step 7:4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylicacid hydrochloride

A mixture of4-(prop-1-en-2-yl)-2-(2,4,6-trimethylbenzyl)isoindoline-1-carboxylicacid hydrochloride (43 mg, 0.12 mmol) and 10% palladium on carbon (5 mg,0.005 mmol) in methanol (3 mL) was stirred under an atmosphere ofhydrogen for 5 h. The reaction mixture was filtered and subjected topreparatory-HPLC (10-99% acetonitrile/water with 0.05 mM HCl) to give4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylicacid hydrochloride (28 mg, 65%) as a colorless solid. ESI-MS m/z talc.337.2, found 338.2 (M+1)⁺; Retention time: 0.55 min (1 min run).

Step 8:4-isopropyl-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 218)

A mixture of4-isopropyl-2-(2,4,6-trimethylbenzyl)isoindoline-1-carboxylic acidhydrochloride (28 mg, 0.075 mmol) and sodium carbonate (24 mg, 0.22mmol) in N,N-dimethylformamide (1 mL) was degassed with a stream ofnitrogen for 1 min before addingN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (34 mg, 0.090 mmol). The mixture wasdegassed for 1 min and 2-methoxypyridine-3-sulfonamide (21 mg, 0.11mmol) was added to the reaction mixture. The mixture was degassed for 1min before it was stirred at room temperature for 17 h. The reactionmixture was filtered and subjected to preparatory-HPLC (10-99%acetonitrile/water with 0.05 mM HCl) to give4-isopropyl-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 218) (16 mg, 42%). ESI-MS m/z talc. 507.2, found 508.4 (M+1)⁺;Retention time: 0.68 min (1 min run).

Step 9:4-isopropyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 103)

A mixture of4-isopropyl-N4(2-methoxypyridin-3-yl)sulfonyl)-2-(2,4,6-trimethylbenzyl)isoindoline-1-carboxamide(16 mg, 0.032 mmol) in acetic acid (1 mL) and HBr (46 μL of 33%w/v, 0.19mmol) (in acetic acid) was stirred at 50° C. for 1 h. The solvent wasevaporated and the residue was subjected to preparatory-HPLC (10-99%acetonitrile/water with 0.05 mM HCl) to give4-isopropyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(Compound 103) (12 mg, 69%). ESI-MS m/z calc. 493.2, found 494.3 (M+1)⁺;Retention time: 1.44 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-(3-aminophenyl)sulfonyl-4-ethyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 30),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-4-phenyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 508),-   N-[(2-methoxy-3-pyridyl)sulfonyl]-4-phenyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 427),-   N-[(6-amino-2-pyridyl)sulfonyl]-4-phenyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 554), and-   N-(3-aminophenyl)sulfonyl-4-isopropyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 299).

PREPARATION 30: 2-(tert-butyl)-4-(mesityloxy)pyrimidine-5-carboxylicacid Step 1: ethyl 2-(tert-butyl)-4-hydroxypyrimidine-5-carboxylate

In EtOH (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g,27.2 mmol). A solution of NaOEt (21% in EtOH, 8.80 g, 27.2 mmol) wasadded and the resulting mixture was stirred 15 min at room temperature.Diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionmixture was heated at reflux for 1 h and then the solvent was removed.The residue was dissolved in water (100 mL) and the pH adjusted to 3-4with NaHSO₄ (1M). The solid was collected by filtration, washed withwater (50 mL) and dried. The filtrate and washings were combined andextracted with ethyl acetate (2×150 mL). The combined extracts weredried over Na₂SO₄, filtered and concentrated. The residue plus the solidcollected during filtration were subjected to column chromatography onsilica gel, eluted with CH₂Cl₂/hexanes/methanol (50/50/0 to 45/45/10) toafford ethyl 2-(tert-butyl)-4-hydroxypyrimidine-5-carboxylate (2.85 g,60%). ¹H NMR (250 MHz, CDCl₃) δ 8.74 (s, 1H), 4.36 (q, J=7.3 Hz, 2H),1.43 (s, 9H), 1.37 (t, J=7.2 Hz, 3H).

Step 2: ethyl 2-(tert-butyl)-4-chloropyrimidine-5-carboxylate

At 0° C., Et₃N (1.1 mL) was added to POCl₃ (32 mL), followed by theaddition of ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (3.70g, 16.5 mmol). The mixture was stirred at 40° C. for 1 h and the excessPOCl₃ was removed under vacuum. The residue was carefully poured intoice (400 mL) and was extracted with CH₂Cl₂. The extract was washed withNaHCO₃ and water, dried over Na₂SO₄, filtered and concentrated. Thecrude material was subjected to silica gel column chromatography (10-90%CH₂Cl₂/hexanes) to afford ethyl2-(tert-butyl)-4-chloropyrimidine-5-carboxylate (3.8 g, 95%) as aliquid. (M+1)⁺=243.4.

Step 3: 2-tert-butyl-4-(2,4,6-trimethylphenoxy)pyrimidine-5-carboxylate

2,4,6-Trimethylphenol (2.10 g, 15.4 mmol) and sodium hydride (60%, 690mg, 17.3 mmol) were combined in an anhydrous mixture ofN,N-dimethylformamide (20 mL) and tetrahydrofuran (2 mL). The reactionmixture was stirred at room temperature for 15 min under an atmosphereof nitrogen. Ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (3.80g, 15.7 mmol) was added and the reaction mixture was heated at 60° C.for 1 h. The reaction mixture was then allowed to cool to roomtemperature. The reaction mixture was diluted with water and extractedwith ethyl acetate. The ethyl acetate layer was washed three times withwater, dried over sodium sulfate, filtered and concentrated. The crudematerial was purified by silica gel column chromatography (0-30% ethylacetate/hexanes) to yield ethyl2-tert-butyl-4-(2,4,6-trimethylphenoxy)pyrimidine-5-carboxylate (3.1 g,58%) as a liquid. ESI-MS m/z 351 (M₊1)⁺; ¹H NMR (250 MHz, CDCl₃) δ 9.07(s, 1H), 6.88 (s, 2H), 4.43 (q, J=7.2 Hz, 2H), 2.30 (s, 3H), 2.21 (s,6H), 1.40 (t, J=7.2 Hz, 3H), 1.17 (s, 9H).

Step 4: 2-tert-butyl-4-(2,4,6-trimethylphenoxy)pyrimidine-5-carboxylicacid

Ethyl 2-tert-butyl-4-(2,4,6-trimethylphenoxy)pyrimidine-5-carboxylate(3.1 g, 9.1 mmol) was combined in a mixture of methanol (25 mL) andwater (30 mL) containing sodium hydroxide (1.2 g, 30 mmol). Theresulting suspension was heated at 60° C. for 3 h. The reaction mixturewas cooled to room temperature and was made acidic with 6M hydrochloricacid. The resulting precipitate was filtered, washed with water anddried to yield2-tert-butyl-4-(2,4,6-trimethylphenoxy)pyrimidine-5-carboxylic acid (2.2g, 77%) as a white solid. ESI-MS m/z 315 (M+1)⁺; ¹H NMR (250 MHz, DMSO)9.01 (s, 1H), 6.95 (s, 2H), 2.27 (s, 3H), 1.98 (s, 6H), 1.11 (s, 9H).

The following compound can be synthesized using the procedures describedherein:N-(3-aminophenyl)sulfonyl-2-tert-butyl-4-(2,4,6-trimethylphenoxy)pyrimidine-5-carboxamide(Compound 68).

PREPARATION 31:4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-imidazole-2-carboxylicacid Step 1: 4-tert-butyl-1H-imidazole

A mixture of 1-bromo-3,3-dimethylbutan-2-one (2.00 g, 11.2 mmol) informamide (10 mL) was heated between 160-180° C. in a sealed tubeequipped with a safety pressure release mechanism for 5 h. The mixturewas cooled to room temperature and was poured into 10% aqueous sodiumbicarbonate (30 mL). The solution was extracted with dichloromethane(2×30 mL). The combined organic layers were washed with 10% potassiumcarbonate, brine, dried over Na₂SO₄ , filtered and concentrated underreduced pressure to provide 4-tert-butyl-1H-imidazole (1.37 g, 99%) asan oil. ¹H NMR (300 MHz, CDCl₃) δ 1.31 (s, 9H), 6.76 (s, 1H), 7.56 (s,1H), 9.63 (br.s., 1H).

Step 2: 4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-imidazole

To 4-ten-butyl-I H-imidazole (1.37 g, 11.0 mmol) and cesium carbonate(7.20 g, 22.0 mmol) in acetonitrile (24 mL) was added2-(bromomethyl)-1,3,5-trimethyl benzene (1.58 g, 9.38 mmol). Theresulting suspension was stirred at room temperature overnight. Heptane(10 mL) was added to the reaction mixture before it was filtered througha pad of silica and washed with a 1:1 mixture of ethyl acetate:heptane.The eluent was concentrated to provide4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-imidazole (1.47g, 52%)as an oil. ¹H NMR (300 MHz, DMSO) 61.15 (s, 9H), 2.26 (s, 6H), 2.29 (s,3H), 5.02 (s, 2H), 6.43 (s, 1H), 6.90 (s, 2H), 7.23 (s, 1H).

Step 3:4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-imidazole-2-carboxylicacid

To a solution of4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-imidazole (1.40 g,5.46 mmol) in anhydrous THF (40 mL) was added n-BuLi (2.5 M, 2.62 mL,6.55 mmol) at 78° C. The reaction mixture was stirred at −78° C. for 1H.A piece of dry ice was added in one portion at −78° C. The solution wasstirred for 20 min at −78° C., and then the reaction mixture was allowedto reach to room temperature and was stirred under a CO₂ atmosphere for2 h. The mixture was quenched with water (50 mL) and 1N HCl (7 ml) andthen stirred for 10 min. The mixture was extracted with ethyl acetate(100 mL). The organic layer was separated from the aqueous phase andthen concentrated under reduced pressure. The residue was trituratedwith CH₂Cl₂, concentrated, and then triturated again with methyltert-butyl ether. The solid was washed with methyl tert-butyl ether anddried under reduced pressure to provide4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-imidazole (588 mg,34%) as a white solid. NMR (300 MHz, CDCl₃) δ1.23 (s, 9H), 2.16 (s, 6H),2.22 (s, 3H), 5.76 (s, 2H), 6.27 (s, 1H), 6.91 (s, 2H).

The following compound can be synthesized using the procedures describedherein:N-(3-aminophenyl)sulfonyl-4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]imidazole-2-carboxamide(Compound 255).

PREPARATION 32:4,4-dimethyl-2-[(2,4,6-trimethylphenyl)methyl]-1,3-dihydroisoquinoline-1-carboxylicacid Step 1: methyl (2-methyl-2-phenylpropyl)carbamate

Methyl carbonochloridate (518 μL, 6.70 mmol) was added to a solution of2-methyl-2-phenyl-propan-1-amine (1.00 g, 6.70 mmol) and pyridine (813μL, 10.1 mmol) in CH₂Cl₂ (25 mL) at 0° C. The mixture was allowed tostir at room temperature for 1 h before it was quenched with 1N HCl. Themixture was washed with 1N HCl (2×25 mL), brine, dried over sodiumsulfate, filtered and concentrated to give methyl(2-methyl-2-phenylpropyl)carbamate (911 mg, 66%). ESI-MS m/z calc.207.1, found 208.4 (M+1)⁺; Retention time: 0.54 min (1 min run).

Step 2:2-methoxycarbonyl-4,4-dimethyl-1,3-dihydroisoquinoline-1-carboxylic acid

Methyl (2-methyl-2-phenylpropyl)carbamate (911 mg, 4.40 mmol) wassuspended in acetic acid (15 mL) and H₂SO₄ (5 mL). The mixture wascooled to 0° C. before oxaldehydic acid hydrate (679 mg, 7.37 mmol) wasadded. The reaction mixture was allowed to warm to room temperature over1H and was stirred at room temperature for an additional 2 h. Thereaction mixture was poured over ice which and the mixture was extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated to give2-(methoxycarbonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid (1.1 g, 79%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.55 (s,1H), 7.45-7.17 (m, 3H), 5.66 (d, J=35.8 Hz, 1H), 3.90 (d, J=94.9 Hz,4H), 3.33 (s, 1H), 1.28 (d, J=51.5 Hz, 6H). ESI-MS m/z calc. 263.1,found 264.0 (M+1)⁺; Retention time: 1.27 min (3 min run).

Step 3: 4,4-dimethyl-2,3-dihydro-1H-isoquinoline-1-carboxylic acid

Iodo(trimethyl)silane (254 μL, 1.78 mmol) was added to2-methoxycarbonyl-4,4-dimethyl-1,3-dihydroisoquinoline-1-carboxylic acid(412 mg, 1.49 mmol) in chloroform (10 mL). The mixture was heated at 65°C. for 2 h. Additional iodo(trimethyl)silane (254 μL, 1.78 mmol) wasadded and the reaction mixture was heated at 65° C. for 2 h. Thereaction mixture was concentrated and the residue was subjected topreparatory-HPLC (10-99% acetonitrile/water with 0.05 mM HCl) to give4,4-dimethyl-2,3-dihydro-1H-isoquinoline-1-carboxylic acid (261 mg,85%). ESI-MS m/z calc. 205.1, found 206.4 (M+1)⁺; Retention time: 0.27min (1 min run).

Step 4:4,4-dimethyl-2-[(2,4,6-trimethylphenyl)methyl]-1,3-dihydroisoquinoline-1-carboxylicacid

A suspension of 4,4-dimethyl-2,3-dihydro-1H-isoquinoline-1-carboxylicacid (260 mg, 1.27 mmol) and KOH (213 mg, 3.80 mmol) in isopropanol (1.6mL) was stirred at room temperature for 20 min.2-(Chloromethyl)-1,3,5-trimethylbenzene (235 mg, 1.39 mmol) was addedand the reaction mixture was stirred for 3 h. The mixture wasconcentrated and the residue was subjected to preparatory-HPLC (10-99%acetonitrile/water with 0.05 mM HCl) to give4,4-dimethyl-2-(2,4,6-trimethylbenzyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid. ESI-MS m/z calc. 337.2, found 338.0 (M+1)⁺; Retention time: 1.42min (3 min run).

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-4,4-dimethyl-2-[(2,4,6-trimethylphenyl)methyl]-1,3-dihydroisoquinoline-1-carboxamide    (Compound 140).

PREPARATION 33: 4-tert-butyl-2-(2,4,6-trimethylphenoxy)benzoic acid

A mixture of 2-bromo-4-tert-butyl-benzoic acid (500 mg, 1.95 mmol),2,4,6-trimethylphenol (397 mg, 2.92 mmol), Cs₂CO₃ (1.27 g, 3.89 mmol),Cu(OTf)₂ (49 mg, 0.097 mmol) and toluene (10 mL) was combined in amicrowave vial before it was sealed and heated at 125° C. for 4 h. Themixture was cooled to room temperature and was partitioned between ethylacetate (50 mL) and water (50 mL). The layers were separated and theaqueous layer was made acid by the addition of 1N HCl. The aqueous layerwas extracted with ethyl acetate (2×30 mL). The combined organics weredried over magnesium sulfate, filtered and concentrated. The residue wassubjected to silica gel column chromatography (0-3% methanol/CH₂Cl₂) togive 4-tert-butyl-2-(2,4,6-trimethylphenoxy)benzoic acid (250 mg, 39%)as a white solid. ESI-MS m/z calc. 312.2, found 313.4 (M+1)⁺; Retentiontime: 2.14 min (3 min run). ¹H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 7.73(d, J=8.2 Hz, 1H), 7.07 (dd, J=8.2, 1.8 Hz, 1H), 6.99 (s, 2H), 6.35 (d,J=1.7 Hz, 1H), 2.28 (s, 3H), 2.01 (s, 6H), 1.10 (s, 9H).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-(3-aminophenyl)sulfonyl-4-tert-butyl-2-(2,4,6-trimethylphenoxy)benzamide    (Compound 224)-   and    N-[(6-amino-2-pyridyl)sulfonyl]-4-tert-butyl-2-(2,4,6-trimethylphenoxy)benzamide    (Compound 102).

PREPARATION 34:4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrrole-2-carboxylicacid Step 1: ethyl5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylate

To a solution of gallium trichloride (4.00 g, 22.7 mmol) in carbondisulfide (30 mL) at room temperature were added ethylpyrrole-2-carboxylate (2.87 g, 20.6 mmol) and 2-chloro-2-methylpropane(2.50 mL, 23.0 mmol). The mixture was then heated at reflux for 45 min.The reaction mixture was cooled to room temperature and was poured ontoa mixture of ice and 1N HCl. The aqueous layer was extracted withdichloromethane. The organic layer was washed with saturated NaHCO₃,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (0-10% ethylacetate/heptanes) to afford 4-tert-butyl-1H-pyrrole-2-carboxylate (260mg, 7%), ethyl 5-tert-butyl-1H-pyrrole-2-carboxylate (2.1 g, 52%) andethyl 3,5-di-tert-butyl-1H-pyrrole-2-carboxylate (352 mg, 7%) eachisolated as white solids. Ethyl 4-tert-butyl-1H-pyrrole-2-carboxylate:¹H NMR (300 MHz, CDCl₃) δ 1.25 (s, 9H), 1.35 (t, J=7.1 Hz, 3H), 4.30 (q,=7.1 Hz, 2H), 6.76 (dd, J=2.7, 1.8 Hz, 1H), 6.85 (dd, J=2.3, 1.9 Hz,1H), 8.83 (br. s, 1H).

Step 2: ethyl4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrrole-2-carboxylate

Sodium hydride (24 mg as a 60% dispersion in mineral oil, 0.60 mmol) wasadded to a solution of ethyl 4-tert-butyl-1H-pyrrole-2-carboxylate(0.10g, 0.51 mrnol) in N,N-dimethylformamide (3 mL) at 0° C. The mixturewas allowed to stir at 0° C. for 5 min before it was stirred at roomtemperature for 30 min. 2,4,6-Trimethylbenzyl bromide (0.12 g, 0.55mmol) was added portion-wise and the mixture was stirred at roomtemperature for 20 h. The reaction mixture was quenched at 0° C. withaqueous saturated NH₄Cl (4 mL). The mixture was extracted with ethylacetate (80 mL) and the organic layer was washed with brine (2×30 mL)and water (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(0-15% ethyl acetate/heptanes) to afford4-ten-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrrole-2-carboxylate(161 mg, 98%) as a white solid. NMR (300 MHz, CDCl₃) δ 1.12 (s, 9H),1.38 (t, J=7.1 Hz, 3H), 2.20 (s, 6H), 2.31 (s, 3H), 4.31 (q, J=7.1 Hz,2H), 5.47 (s, 2H), 6.11 (d, J=2.1 Hz, 1H), 6.91 (s, 2H), 6.92 (d, J=2.1,1H).

Step 3:4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrrole-2-carboxylicacid

To a solution of ethyl4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrrole-2-carboxylate(97 mg, 0.29 mmol) in methanol (6.3 mL) at room temperature was added a1.0 N solution of NaOH (5.5 mL) and the mixture was heated at reflux for4 hours. The mixture was cooled at room temperature and diluted withwater (40 mL). The pH was adjusted to 4-5 using 1.0 N HCl and theaqueous layer was extracted with ethyl acetate (120 mL). The organiclayer was washed with water (2×40 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The solid was triturated withdiethyl ether to provide4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrrole-2-carboxylicacid (74 mg, 84%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.12 (s,9H), 2.21 (s, 6H), 2.32 (s, 3H), 5.47 (s, 2H), 6.18 (d, J=2.0 Hz, 1H),6.91 (s, 2H), 7.06 (d, J=2.0 Hz, 1H).

The following compounds can be synthesized using the proceduresdescribed herein:N-(benzenesulfonyl)-4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrole-2-carboxamide(Compound 242) andN-(3-aminophenyl)sulfonyl-4-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrole-2-carboxamide(Compound 195).

PREPARATION 35:2-(tert-butyl)-5-(2,4,6-trimethylbenzyl)oxazole-4-carboxylic acid Step1: ethyl 2-hydroxy-2-pivalamidoacetate

Acetic acid (2.61 g, 44.5 mmol) was added to a suspension oftrimethylacetarnide (9.00 g, 89.1 mmol) and ethyl glyoxylate (50% intoluene, 27.6 g, 133 mmol) in THF (60 mL). The mixture was heated atreflux for 16 h before it was cooled and concentrated to dryness. Theresidue was treated with heptanes and diethyl ether (10:1 ratio, 110 mL)to give a precipitate which was removed by filtration. The filtrate wasconcentrated to afford ethyl 2-hydroxy-2-pivalamidoacetate (16.8 g) as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 1.22 (s, 9H), 2.27-1.35 (m,3H), 3.63-3.75 (m, 1H), 4.20-4.36 (m, 2H), 5.50-5.60 (m, 1H), 6.65 (brs, 1H). LC-MS analysis: (M+1)=204.1.

Step 2: ethyl 2-chloro-2-pivalamidoacetate

Thionyl chloride (28.6 g, 242 mmol) was added to a solution of ethyl2-hydroxy-2-pivalamidoacetate (18.6 g, 80.8 mmol) andN,N-dimethylformamide (1 mL) in CH₂Cl₂ (100 mL) at 0° C. The mixture wasstirred at room temperature for 16 h before it was concentrated todryness to afford ethyl 2-chloro-2-pivalamidoacetate (20 g, 64%) as ayellow oil. ¹H NMR (300 MHz, CDCl₃) δ 1.27 (s, 9H), 1.29-1.37 (m, 3H),4.20-4.36 (m, 2H), 6.25 (d, J=9.8, 1H), 6.85 (br s, 1H).

Step 3: ethyl 5-amino-2-(tert-butyl)oxazole-4-carboxylate

Diethylalurninum cyanide (1N in toluene, 76.6 mL, 76.7 mmol) was addedto a solution of ethyl 2-chloro-2-(2,2-dimethylpropanamido)acetate (11.3g, 2.71 mmol) in THF (110 mL) at 0° C. The mixture was stirred at roomtemperature for 16 h before sat. aqueous NH₄Cl (4 mL) was added to thereaction mixture. The mixture was filtered through Celite and thefiltrate was extracted with ethyl acetate (200 mL). The organic layerwas washed with brine, dried over Na₂SO₄, filtrated and concentrated.The residue was purified by silica gel column chromatography (50% ethylacetate/heptane) to afford ethyl5-amino-2-tert-butyl-1,3-oxazole-4-carboxylate (3.21 g, 30%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 1.32 (s, 9H), 1.33-1.38 (m, 3H),4.28-4.38 (m, 2H), 5.42 (br s, 2H). LC-MS analysis: [M+H]⁺=213.1.

Step 4: ethyl 5-bromo-2-(tert-butyl)oxazole-4-carboxylate

A mixture of ethyl 5-amino-2-tert-butyl-1,3-oxazole-4-carboxylate (1.50g, 7.06 mmol) and CuBr₂ (1.59 g, 7.12 mmol) in acetonitrile (25 mL) wasstirred at room temperature for 1 h followed by addition of tert-butylnitrite (0.94 g, 9.2 mmol). The mixture was stirred at room temperaturefor 1 h, and then heated at 65° C. for 2.5 h. Brine was added to thereaction mixture and it was extracted with diethyl ether (200 mL). Theorganic layer was washed by brine spiked with a few drops of 1N HCl,dried over Na₂SO₄, filtrated and concentrated. The residue was purifiedby silica gel column chromatography (15% ethyl acetate/hexanes) toafford ethyl 5-bromo-2-tert-butyl-1,3-oxazole-4-carboxylate (1.31 g,56%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 1.19-1.23 (m, 3H), 1.25(s, 911), 4.38 (q, J=6.8 Hz, 2H). LC-MS analysis: (MI-1)⁺=276.0.

Step 5: ethyl2-(tertsbutyl)-5-(2,4,6-trimethylbenzypaxazole-4-carboxylate

A mixture of ethyl 5-bromo-2-tert-butyl-1,3-oxazole-4-carboxylate (1.15g, 4.18 mmol), Pd(OAc)₂ (0.09 g, 0.4 mmol) and ^(t)BuP-HBF₄ (0.24 g,0.83 mmol) in THF (10 mL) was evacuated and back-filled with N₂ threetimes. The mixture was cooled to 0° C. and(2,4,6-trimethylbenzyl)zinc(II) bromide (1M in THF, 8.36 mL, 8.36 mmol)was added slowly. The mixture was allowed to warm to room temperatureand it was stirred for 16 h. The mixture was concentrated and theresidue was subjected to silica gel column chromatography (15% ethylacetate/heptanes) to afford ethyl2-tert-butyl-5-[(2,4,6-trimethylphenyl)methyl]-1,3-oxazole-4-carboxylate(0.48 g, 31%) as yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 1.27 (s, 9H),1.41 (t, J=6.9 Hz, 311), 2.25 (s, 3H), 2.31 (s, 6H), 4.35 (s, 2H), 4.42(q, J=7.2 Hz, 2H), 6.85 (s, 2H). LC-MS analysis: (M+1)⁺=300.2.

Step 6: 2-(tent-butyl)-5-(2,4,6-trimethylbenzypoxazole-4-carboxylic acid

A mixture of ethyl2-tert-butyl-5-[(2,4,6-trimethylphenyl)methyl]-1,3-oxazole-4-carboxylate(0.48 g, 1.5 mmol) and LiOH.H₂O (0,30 g, 7.3 mmol) in THF (4 mL) andwater (4 mL) was stirred at room temperature for 16 h. The mixture wasdiluted with ethyl acetate (150 mL) the the pH was adjusted ˜4 using 5%citric acid. The organic layer was washed with brine, dried over Na₂SO₄,filtrated and concentrated. The residue was triturated with diethylether and hexanes (8:1, 9 mL) to give2-tert-butyl-5-[(2,4,6-trimethylphenyl)methyl]-1,3-oxazole-4-carboxylicacid (0.33 g, 75%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.28 (s,9H), 2.25 (s, 3H), 2.33 (s, 6H), 4.37 (s, 2H), 6.85 (s, 2H). LC-MSanalysis: (M+1)⁺=302.2.

The following compound can be synthesized using the procedures describedherein:N-(3-aminophenyl)sulfonyl-2-tert-butyl-5-[(2,4,6-trimethylphenyl)methyl]oxazole-4-carboxamide(Compound 360).

PREPARATION 36: lithium3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-1,2,4-triazole-5-carboxylateStep 1:2,2-dimethyl-N%[(1E)-2,4,6-trimethylphenyl)methylidene]-propanehydrazide

To a solution of 2,4,6-trimethylbenzaldehyde (2.96 g, 20.0 mmol) in1,2-dichloroethane (16 mL) at room temperature was added2,2-dimethylpropionic acid hydrazide (2.32 g, 20.0 mmol) and the mixturewas stirred for 2 h at room temperature during which time a whiteprecipitate formed. Diethyl ether (30 mL) was added to facilitateprecipitation and stirring was continued for 1 h. Filtration over afritted funnel, followed by washing of the solids with diethyl ether (30mL) and drying under high vacuum afforded2,2-dimethyl-AP-[(1E)-2,4,6-trimethylphenyl)methylidene]propanehydrazide(4.33 g, 88%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ1.33 (s, 9H),2.28 (s, 3H), 2.45 (s, 6H), 6.87 (s, 2H), 8.52 (br. s, 1H), 8.61 (br. s,1H). (M+1)⁺=247.2.

Step 2: 2,2-dimethyl-N′-[(2,4,6-trimethylphenyl)methyl]-propanehydrazide

To a solution of2,2-dimethyl-N′-[(1E)-2,4,6-trimethylphenyl)methylidene]-propanehydrazide(4.33 g, 17.6 mmol) in methanol (90 mL) was added 10% palladium oncarbon (dry basis, 230 mg, 0.21 mmol). The reaction mixture was purgedwith hydrogen (3 cycles of vacuum/hydrogen) then stirred at roomtemperature for 2 h under an atmosphere of hydrogen. The reactionmixture was filtered over Celite, washed with methanol and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (0-35% ethyl acetate/heptanes) to afford2,2-dimethyl-N′-[(2,4,6-trimethylphenyl)methyl]propanehydrazide (3.76 g,86%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.20 (s, 9H), 2.26 (s,3H), 2.43 (s, 6H), 3.97 (s, 2H), 4.59 (br. s, 1H), 6.86 (s, 2H), 7.14(br. s, 1H). (M+1)⁺=249.2.

Step 3: ethyl3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-1,2,4-triazole-5-carboxylate

Triethyloxonium tetrafluoroborate (3.42 g, 18.0 mmol) was addedportion-wise to a solution of ethyl thiooxamate (2.28 g, 17.1 mmol) inCH₂Cl₂ (35 mL). The resulting mixture was stirred at room temperaturefor 20 h. The mixture was then cooled to 0° C., and a solution of2,2-dimethyl-N′-[(2,4,6-trimethylphenyl)methyl]propanehydrazide (4.48 g,18.0 mmol) and triethylamine (2.5 mL, 18 mmol) in CH₂Cl₂ (20 mL) wasadded slowly, followed by an additional portion of triethylamine (1.3mL, 9.0 mmol). The reaction mixture was then heated at reflux for 20 h.The crude mixture was concentrated under reduced pressure and theresulting yellow oil was purified by silica gel column chromatography(0-40% ethyl acetate/heptanes) to afford a solid. Reverse phasechromatographic separation with mixtures of 40% to 95% CH₃CN in watercontaining 0.1% formic acid afforded ethyl3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-1,2,4-triazole-5-carboxylate(620 mg, 11%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.29 (s, 9H),1.43 (t, J=7.1 Hz, 3H), 2.27 (s, 3H), 2.31 (s, 6H), 4.49 (q, J=7.1 Hz,2H), 5.71 (s, 2H), 6.86 (s, 2H). (M+1)⁺=330.2.

Step 4: lithium3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-1,2,4-triazole-5-carboxylate

To a flask containing ethyl3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-1,2,4-triazole-5-carboxylate(110 mg, 0.33 mmol) and LiOH monohydrate (17 mg, 0.40 mmol) weresuccessively added THF (2 mL) and water (1 mL) followed by one drop ofmethanol. The mixture was stirred at room temperature for 1 h. Thevolatiles (mostly THF and methanol) were removed under reduced pressure,then the mixture was frozen in a dry-ice/acetone bath and freeze-driedto afford lithium3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-1,2,4-triazole-5-carboxylate(98 mg, 95%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.24 (s, 9H),2.24 (s, 3H), 2.33 (s, 6H), 5.73 (s, 2H), 6.82 (s, 2H).

The following compound can be synthesized using the procedures describedherein:

-   N-(3-aminophenyl)sulfonyl    -5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]-1,2,4-triazole-3-carboxamide    (Compound 261).

PREPARATION 37: 5-(tert-butyl)-3-(mesityloxy)pyrazine-2-carboxylic acidStep 1: 3,3-dimethylbutane-1,2-diamine dihydrochloride

A mixture of 2-amino-3,3-dimethyl-butyronitrile hydrochloride (2.94 g,20.0 mmol), HCl (sat. in EtOH, 10 nth), PtO₂ (600 mg) and methanol (200mL) at room temperature was treated with hydrogen (50 psi) for 18 h. Thereaction mixture was filtered through a pad of Celite and the filtratewas evaporated to give 3,3-dimethylbutane-1,2-diamine dihydrochloride asa white solid (3.9 g, 79%).

Step 2: ethyl 5-(tert-butyl)-3-hydroxypyrazine-2-carboxylate

A mixture of 3,3-Dimethyl-butane-1,2-diamine dihydrochloride (3.9 g, 21mmol), 2-oxo-malonic acid diethyl ester (3.45 mL, 22.7 mmol), Et₃N (5.8mL, 41 mmol) and. EtOH (400 mL) was heated at reflux for 20 h. Allvolatiles were removed and the residue was subjected to silica gelcolumn chromatography (0-30% ethyl acetate/hexanes) (0/100 to 30/70) togive ethyl 5-(tert-butyl)-3-hydroxypyrazine-2-carboxylate (0.59 g, 13%)as a sticky oil, which solidified on standing. ¹H NMR (250 MHz, CDCl₃) δ8.36 (s, 1H), 4.55 (q, J=7.2 Hz, 2H), 1.49 (t, J=7.2 Hz, 3H), 1.41 (s,9H).

Step 3: ethyl 5-(tert-butyl)-3-chloropyrazine-2-carboxylate

A mixture of ethyl 5-(tert-butyl)-3-hydroxypyrazine-2-carboxylate (590.mg, 2.63 mmol) and POCl₃ (10 mL) was heated at reflux for 5 h. Theexcess POCl₃ was removed under reduced pressure and the residue waspartitioned between ethyl acetate and aq. NaHCO₃ (pH adjusted to 6 byaddition of sodium carbonate). The organic phase was separated, driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedby silica gel column chromatography (0-30% ethyl acetate/hexanes) togive ethyl 5-(tert-butyl)-3-chloropyrazine-2-carboxylate (90 mg, 14%).¹H NMR (250 MHz, CDCl₃) δ 8.59 (s, 1H), 4.49 (q, J=7.2 Hz, 2H), 1.44 (t,J=7.2 Hz, 3H), 1.40 (s, 9H).

Step 4: 5-tert-butyl-3-(2,4,6-trimethylphenoxy)pyrazine-2-carboxylicacid

2,4,6-Trimethylphenol (51 mg, 0.38 mmol) and sodium hydride (18 mg, 0.45mmol) were combined in anhydrous N,N-dimethylformamide (3 mL). Thereaction mixture was stirred at room temperature for 15 mM under anatmosphere of nitrogen. Ethyl5-tert-butyl-3-chloro-pyrazine-2-carboxylate (90. mg, 0.37 mmol) intetrahydrofuran (1 mL) was then added and the reaction mixture washeated at 60° C. for 1 h. To this mixture was added water (1 mL) andNaOH (120 mg). The resulted mixture was stirred at 70° C. for 1 h andwas cooled to room temperature. The mixture was treated with HCl (1 M)to pH 3 and the mixture was extracted with ethyl acetate (3×). Thecombined extracts were concentrated to about 1 mL (N,N-dimethylformamidepresent). The residue was subjected to preparatory-HPLC (10-99%acetonitrile/water with 0.05 mM HCl) to give5-tert-butyl-3-(2,4,6-trimethylphenoxy)pyrazine-2-carboxylic acid (55mg, 47%). ¹HNMR (250 MHz, DMSO) δ 8.41 (s, 1H), 6.94 (s, 2H), 2.26 (s,3H), 1.97 (s, 6H), 1.11 (s, 9H).

The following compound can be synthesized using the procedures describedherein:

-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-3-(2,4,6-trimethylphenoxy)pyrazine-2-carboxamide    (Compound 141).

PREPARATION 38: 5-(tert-butyl)-3-(mesityloxy)pyrazine-2-carboxylic acidStep 1: ethyl 6-(tert-butyl)-4-chloronicotinate

A solution of ethyl 6-tert-butyl-1,4-dihydro-4-oxopyridine-3-carboxylate(1.0 g, 4.5 mmol) and phosphorus oxychloride (10 mL) was heated at 110°C. for 1.5 h. The reaction solution was cooled to room temperature andwas concentrated under reduced pressure. The residue was cooled to 0° C.before water (20 mL) and enough saturated aqueous NaHCO₃ were carefullyadded to bring the mixture to pH ˜8. The mixture was extracted withethyl acetate (3×). The combined organics were dried over MgSO₄,filtered, and concentrated under vacuum to give ethyl6-(tert-butyl)-4-chloronicotinate (0.80 g, 73%) as a brown oil. ¹H NMR(CDCl₃, 250 MHz) δ 8.99 (s, 1H), 7.40 (s, 1H), 4.41 (m, 2H), 1.36 (m,12H). LC-MS: (M+1)⁺=242.2.

Step 2: 6-tert-butyl-4-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate

To a solution of 2,4,6-trimethylphenol (0.43 g, 3.1 mmol) inN,N-dimethylformamide (4 mL) and THF (1 mL) was added slowly 60% NaH(0.15 g, 3.9 mmol). The mixture was stirred at room temperature for 25min before ethyl ethyl 6-(tert-butyl)-4-chloronicotinate (0.74 g, 3.1mmol) was added. The reaction mixture was stirred at 60° C. for 1 hbefore it was cooled to room temperature and quenched by adding water.The mixture was extracted with ethyl acetate (3×). The combined organicextracts were concentrated and the residue was purified by silica gelcolumn chromatography (0-20% ethyl acetate/hexanes) to afford ethyl6-tert-butyl-4-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (0.45 g,43%) as a light yellow oil. LC-MS: (M+1)⁺=341.9.

Step 3: 6-tert-butyl-4-(2,4,6-trimethylphenoxy)pyridine-3-carboxylicacid

A solution of 6-(tert-butyl)-4-(mesityloxy)nicotinate (0.74 g, 2.2 mmol)and sodium hydroxide (0.21 g, 5.2 mmol) in EtOH (2 mL) and water (1 mL)was stirred at room temperature for 3 h. The reaction was concentratedand the residue was acidified with concentrated HCl to about pH 3. Thecrude material was purified by silica gel column chromatography (ethylacetate) to give6-tert-butyl-4-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (0.38g, 55%) as a white solid. ¹H NMR (CDCl₃, 250 MHz) δ 9.22 (s, 1H), 6.96(s, 2H), 6.24 (s, 1H), 2.34 (s, 3H), 2.09 (s, 6H), 1.22 (s, 9H). LC-MS:(M+1)⁺=314.1.

The following compound can be synthesized using the procedures describedherein:N-(3-aminophenyl)sulfonyl-6-tert-butyl-4-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 338).

PREPARATION 39:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 368) andN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1289) Step 1: tert-butyl2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate

tert-Butyl 2,6-dichloropyridine-3-carboxylate (15.0 g, 60.5 mmol) and(3-fluoro-5-isobutoxy-phenyl)boronic acid (13.46 g, 63.48 mmol) werecombined and fully dissolved in ethanol (150 mL) and toluene (150 mL). Asuspsension of sodium carbonate (19.23 g, 181.4 mmol) in water (30 mL)was added. Tetrakis(triphenylphosphine)palladium (O) (2.096 g, 1.814mmol) was added under nitrogen. The reaction mixture was allowed to stirat 60° C. for 16 hours. Volatiles were removed under reduced pressure.The remaining solids were partitioned between water (100 mL) and ethylacetate (100 mL). The organic layer was washed with brine (1×100 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure. The material was subjected silica gel column chromatography ona 330 gram silica gel column, 0 to 20% ethyl acetate in hexanesgradient. The material was repurified on a 220 gram silica gel column,isocratic 100% hexane for 10 minutes, then a 0 to 5% ethyl acetate inhexanes gradient to yield tert-butyl2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate (18.87 g,49.68 mmol, 82.2%) was obtained as a colorless oil. ¹H NMR (400 MHz,DMSO-d₆) δ 8.24 (d, J=8.0 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.48 (dd,J=9.4, 2.0 Hz, 2H), 6.99 (dt, J=10.8, 2.2 Hz, 1H), 3.86 (d, J=6.5 Hz,2H), 2.05 (dt, J=13.3, 6.6 Hz, 1H), 1.57 (d, J=9.3 Hz, 9H), 1.00 (t,J=5.5 Hz, 6H). ESI-MS m/z calc. 379.13504, found 380.2 (M+1)⁺; Retentiontime: 2.57 minutes.

Step 2: 2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylicacid

tort-Butyl2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate (18.57 g,48.89 mmol) was dissolved in dichloromethane (200 mL). Trifluoroaceticacid (60 mL, 780 mmol) was added and the reaction mixture was allowed tostir at room temperature for 1 hour. The reaction mixture was stirred at40° C. for 2 hours. The reaction mixture was concentrated under reducedpressure and taken up in ethyl acetate (100 mL). It was washed with asaturated aqueous sodium bicarbonate solution (1×100 mL) and brine(1×100 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was suspended in ethyl acetate (75mL) and washed with aqueous HCl (1 N, 1×75 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The remaining solid (17.7 g) was stirred as a slurry indichloromethane (35 mL) at 40° C. for 30 minutes. After cooling to roomtemperature, the remaining slurry was filtered, and then rinsed withcold dichloromethane to give2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid(11.35 g, 35.06 mmol, 72%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ13.76 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.54-7.47(m, 2H), 7.00 (dt, J=10.8, 2.3 Hz, 1H), 3.87 (d, J=6.5 Hz, 2H), 2.05(dt, J=13.3, 6.6 Hz, 1H), 1.01 (d, J=6.7 Hz, 6H). ESI-MS m/z calc.323.1, found 324.1 (M+1)⁺; Retention time: 1.96 minutes.

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide

2-Chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (3.00g, 9.27 mmol) was dissolved in N,N-dimethylformamide (30.00 mL), and1,1′-carbonyldiimidazole (2.254 g, 13.90 mmol) was added to thesolution. The solution was allowed to stir at 65° C. for 1 hour. In aseparate flask, sodium hydride (444.8 mg, 11.12 mmol) was added to asolution of 6-aminopyridine-2-sulfonamide (1.926 g, 11.12 mmol) inN,N-dimethylformamide (15.00 mL). This mixture was stirred for one hourbefore being added to the prior reaction mixture. The final reactionmixture was stirred at 65° C. for 15 minutes. Volatiles were removedunder reduced pressure. The remaining oil was taken up in ethyl acetateand washed with aqueous HCl (1 N, 1×75 mL) and brine (3×75 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The remaining white solid (4.7 g) was fullydissolved in isopropanol (120 mL) in an 85° C. water bath. The colorlesssolution was allowed to slowly cool to room temperature with slowstirring over 16 hours. The crystalline solids that had formed werecollected by vacuum filtration, and then rinsed with cold isopropanol(50 mL). Upon drying,N-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(3.24 g, 6.765 mmol, 73%) was obtained as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 12.78 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.09 (d, J=7.9Hz, 1H), 7.73-7.63 (m, 1H), 7.49 (dd, J=8.6, 1.9 Hz, 2H), 7.21 (d, J=7.3Hz, 1H), 6.99 (dt, J=10.7, 2.2 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.64 (s,2H), 3.86 (d, J=6.5 Hz, 2H), 2.05 (dp, J=13.3, 6.5 Hz, 1H), 1.02 (dd,J=12.7, 6.4 Hz, 6H).

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1289) andN-[(6-amino-2-pyridypsuffonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

N-[(6-Amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(309 mg, 0.645 mmol) was dissolved in dimethylsulfoxide (3.708 mL) andpotassium carbonate (445.9 mg, 3.226 mmol) was slowly added, followed by2,2,4-trimethylpyrrolidine (146.0 mg, 1.290 mmol). The reaction mixturewas sealed and heated at 150° C. for 72 hours. The reaction was cooleddown, diluted with water (50 mL), extracted 3 times with 50 mL portionsof ethyl acetate, washed with brine, dried over sodium sulfate, filteredand evaporated to dryness. The crude material was dissolved in 2 mL ofdichloromethane and purified by on silica gel using a gradient of 0 to80% ethyl acetate in hexanes. The stereoisomers were separated usingsupercritical fluid chromatography on a ChiralPak AD-H (250×4.6 mm), 5μm column using 25% isopropanol with 1.0% diehtylamine in CO₂ at a flowrate of 3.0 mL/min. The separated enationmers were separatelyconcentrated, diluted with ethyl acetate (3 mL) and washed with 1Naqueous hydrochloric acid. The organic layers were dried over sodiumsulfate, filtered, and evaporated to dryness to give the pure compoundsas pale yellow solids.

The first compound to eluet from the SFC conditions given above gaveN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1289) (Hydrochloric Acid (1)) ¹H NMR (400 MHz, DMSO-d6) δ12.47 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.69-7.57 (m, 1H), 7.56-7.46 (m,1H), 7.41 (dt, J=10.1, 1.8 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.21 (d,J=7.2 Hz, 1H), 6.89 (dt, J=10.7, 2.3 Hz, 1H), 6.69 (d, J=8.3 Hz, 1H),3.83 (d, J=6.7 Hz, 2H), 2.61 (dq, J=9.7, 4.9 Hz, 2H), 2.24 (d, J=15.8Hz, 1H), 2.06 (dq, J=13.3, 6.7 Hz, 1H), 1.93-1.82 (m, 1H), 1.61 (s, 3H),1.59 (s, 3H), 1.48-1.33 (m, 1H), 1.32-1.20 (m, 2H), 0.99 (d, J=6.6 Hz,6H), 0.88 (d, J=6.2 Hz, 3H). ESI-MS m/z calc. 555.2, found 556.4 (M+1)⁺;Retention time: 2.76 minutes.

The second compound to eluet from the SFC conditions described abovegaveN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Hydrochloric Acid (1)) ¹H NMR (400 MHz, Chloroform-d) δ 15.49 (s, 1H),8.49 (d, J=8.2 Hz, 1H), 7.75-7.56 (m, 3H), 7.34 (t, J=1.8 Hz, 1H), 7.30(dt, J=9.4, 1.9 Hz, 1H), 6.75-6.66 (m, 2H), 3.95 (s, 1H), 3.78 (d, J=6.5Hz, 2H), 3.42 (s, 1H), 2.88-2.74 (m, 1H), 2.23 (dd, J=12.5, 8.0 Hz, 1H),2.17-2.08 (m, 1H), 1.98-1.87 (m, 1H), 1.55 (s, 3H), 1.39 (s, 3H), 1.31(d, J=6.7 Hz, 3H), 1.05 (d, J=6.7 Hz, 6H). ESI-MS m/z calc. 555.2, found556.4 (M+1)⁺; Retention time: 2.77 minutes. Absolute stereochemistry wasconfirmed by X-ray crystallography.

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide    (Compound 114),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 946),-   N4(6-amino-4-methyl-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1472),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-phenylbutoxy)pyridine-3-carboxamide    (Compound 1686),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-(1-naphthyl)ethylamino]pyridine-3-carboxamide    (Compound 1769),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2-(o-tolypazepan-1-yl]pyridine-3-carboxamide    (Compound 1772),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[3-(cyclopropylmethyl)-2,2-dimethyl-pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1794),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2275),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-[2-(trifluoromethypphenyl]ethoxy]pyridine-3-carboxamide    (Compound 2501),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2-(1,3-benzoxazol-2-yl)phenoxy]pyridine-3-carboxamide    (Compound 2544),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2-cyclohexylcyclohexyl)amino]pyridine-3-carboxamide    (Compound 2599),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-phenyl-1-piperidyl)pyridine-3-carboxamide    (Compound 2615),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-methoxy-4-methyl-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1482),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-tetrahydrofuran-3-ylsulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1640),-   N-cyclopropylsulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1525),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-methoxy-pyridine-3-carboxamide    (Compound 1254),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 171),-   N-[(6-Amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3R)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 233),-   2-(2,5-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 307),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 321),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(2,4-dimethyl-3-pyridyl)oxy]pyridine-3-carboxamide    (Compound 460),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 353),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 355),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1354),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3,3,4-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 435),-   6-(4-ethoxyphenyl)-2-(4-methyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 445),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,3R)-2,3-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 441),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(4-pyridyl)butoxylpyridine-3-carboxamide    (Compound 1687),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-1,2-dihydropyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-3-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-1,2-dihydropyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(3-pyridyl)butoxy]pyridine-3-carboxamide    (Compound 1690),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(2-pyridyl)butoxy]pyridine-3-carboxamide    (Compound 1688),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-pyrazol-1-ylpropoxy)pyridine-3-carboxamide    (Compound 1692),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-phenylbutoxy)pyridine-3-carboxamide    (Compound 1689),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[3-(2-pyridyl)propoxy]pyridine-3-carboxamide    (Compound 1693),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[3-(3-pyridyl)propoxy]pyridine-3-carboxamide    (Compound 1691),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-phenylpropoxy)pyridine-3-carboxamide    (Compound 1694),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,2,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 464),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 476),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[3-(2-pyridyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 489),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(trifluoromethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1556),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)-6-(trifluoromethyl)pyridine-3-carboxamide    (Compound 1635),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(trifluoromethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1550),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-methyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1420),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-methoxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1536),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1607),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide    (Compound 1386),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(propypamino]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 500),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-methyl-4-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 502),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 509),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3,3,5-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 520),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-azabicyclo[2.2.1]heptan-3-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 521),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-propyl-1-piperidyl)pyridine-3-carboxamide    (Compound 522),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R,4S)-4-fluoro-2-methyl-pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1362)-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3S)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 557),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[3-(3,4-difluorophenyl)-1-piperidyl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 558),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(1-piperidyl)pyridine-3-carboxamide    (Compound 567),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[2-(methoxymethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 574),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[2.5]octan-6-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 578),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-indolin-1-yl-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 588),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridine-3-carboxamide    (Compound 1638),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxamide    (Compound 1658),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 596),-   N-[(6-amino-5-hydroxy-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1563),-   N-[(6-amino-5-hydroxy-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1375),-   N-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1588),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   N4(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1593),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1444),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 597),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethyl-3-phenyl-pyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 601),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[4-(methoxymethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 606),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-ethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 619),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-methyl-3-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 625),-   N-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1429),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 647),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[3-(2,2,2-trifluoroethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 656),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2-methyl-pyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 658),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-methyl-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl)pyridine-3-carboxamide    (Compound 675),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-azabicyclo[3.1.1]heptan-3-yl)-6-tert-butyl-pyridine-3-carboxamide    (Compound 1401),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-methoxy-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1483),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-(3-methyldiazirin-3-yl)ethyl-prop-2-ynyl-amino]pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 687),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylpyrroliclin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 689),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-methoxyphenyl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1452),-   N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1396),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[2.5]octan-7-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 703),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-isopropylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 724),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-oxa-7-azaspiro[3.5]nonan-7-yl)pyridine-3-carboxamide    (Compound 729),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-phenyl-1-piperidyl)pyridine-3-carboxamide    (Compound 731),-   2-(3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[b]pyrrol-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 732),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[3.5]nonan-7-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 733),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 736),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(methyl)amino]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 740),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(4-phenyl-1-piperidyl)pyridine-3-carboxamide    (Compound 742),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-fluoro-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 745),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3R)-3-methyl-1-piperidyl]pyridine-3-carboxamide    (Compound 757),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,3S)-2,3-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 764),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(1-phenylethylamino)pyridine-3-carboxamide    (Compound 766),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-methoxyphenyl)sulfonyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1171),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-oxo-1H-pyridin-2-yl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1308),-   N-(3-aminophenyl)sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1184),-   N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 620),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(2-pyridylsulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1063),-   N-(3-aminophenyl)sulfonyl-2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1014),-   2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-methoxyphenyl)sulfonyl-pyridine-3-carboxamide    (Compound 510),-   N-(benzenesulfonyl)-2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 583),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-methoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2430),-   2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-oxo-1H-pyridin-2-yl)sulfonyl]pyridine-3-carboxamide    (Compound 775),-   2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(2-pyridylsulfonyl)pyridine-3-carboxamide    (Compound 1069),-   2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-methoxy-2-pyridyl)sulfonyl]pyridine-3-carboxamide    (Compound 1090),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy    -3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 811),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-spiro[1H-isobenzofuran-3,4′-piperidine]-1′-yl-pyridine-3-carboxamide    (Compound 818),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 834),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3S)-3-methyl-1-piperidyl]pyridine-3-carboxamide    (Compound 836),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[3-(cyclopropylmethoxy)-1-piperidyl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 858),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy    -3-pyridyl)-2-[(3S)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 864),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[4-(cyclopropylmethoxy)-1-piperidyl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 884),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-difluoro-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 889),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 903),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-fluoro-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 913),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 915),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1S,4R)-3-azabicyclo[2.2.1]heptan-3-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 921),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,3,5-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 925),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopropylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 928),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(indan-1-ylamino)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 935),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(azepan-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 940),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 949),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethynyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 954),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethoxy-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 960),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-diethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 971),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 979),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(8-azaspiro[3.4]octan-8-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 987),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3R)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 992),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 994),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-benzyloxy-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1012),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1023),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopentyl(methyl)amino]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1025),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(benzylamino)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1026),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,2,5-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1040),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[4-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 1043),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-isoindolin-2-yl-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1072),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(4-phenoxy-1-piperidyl)pyridine-3-carboxamide    (Compound 1080),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3S)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1081),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1087),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-phenoxypyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1092),-   2-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1107),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-phenylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1112),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[3-(methoxymethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 1116),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-cyclopropyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1132),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1134),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3S,5S)-3,5-dimethyl-1-piperidyl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1136),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3R,5S)-3,5-dimethyl-1-piperidyl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1145),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1182),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1198),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-tert-butylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1206),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3R)-3-phenyl-1-piperidyl]pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-ethoxy-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1214),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy    -3-pyridyl)-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1230),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1247),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1248),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-methylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1271),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[3-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 1274),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1283),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3R)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1322),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,3,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1327),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[3-(3-chlorophenyl)-1-piperidyl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1339),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethyl-3-methyl-1-piperidyl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1341),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[2.4]heptan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1333),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3R,5S)-3,5-dimethyl-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 371),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-piperidyl)pyridine-3-carboxamide    (Compound 380),-   2-(3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[b]pyrrol-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 383),-   methyl    (2S)-1-[3-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyridyl]pyrrolidine-2-carboxylate    (Compound 385),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 398),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-methyl-1-piperidyl]pyridine-3-carboxamide    (Compound 408),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(azepan-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 418),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[3-(methoxymethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 419),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 420),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 421),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(8-oxa-4-azaspiro[4.4]nonan-4-yl)pyridine-3-carboxamide    (Compound 424),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 425),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-phenylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 447),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dihydropyrrol-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 453),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 458),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 473),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 479),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-4-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 488),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]pyridine-3-carboxamide    (Compound 490),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2-(1,1-dimethylpropyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 493),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,5-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 496),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-cyclopropylethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 516),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[3.3]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 527),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethyl-3-methyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 530),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(38)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 547),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 555),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 560),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,4-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 575),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,5S)-3-azabicyclo[3.2.1]octan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 581),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 587),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyrrolidin-1-yl-pyridine-3-carboxamide    (Compound 592),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopropylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 593),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 609),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-tert-butylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 611),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 613),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-ethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 615),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 651),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-cyclopropyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 655),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 657),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-(2-pyridyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 659),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 663),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 678),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-azabicyclo[2.2.1]heptan-3-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 680),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclobutyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 683),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 684),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 694),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethyl-3-phenyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 711),-   N-[(6-amino-2-pyridyl)sulfonyl[-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl[pyridine-3-carboxamide    (Compound 719),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 720),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 735),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 751),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 772),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethyl-3-(trifluoromethyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 780),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 837),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(8-azaspiro[3.4]octan-8-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 845),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 850),-   2-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 857),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 859),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(propyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 881),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 887),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-azabicyclo[3.1.0]hexan-4-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 906),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1S,4R)-3-azabicyclo[2.2.1]heptan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 924),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(9-azaspiro[4.4]nonan-9-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 926),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 931),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,5S)-8-azabicyclo[3.2.1]octan-8-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 934),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[2.5]octan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 953),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 969),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[2.5]octan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 973),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 991),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1004),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1-methylcyclopropyl)methyl]amino]pyridine-3-carboxamide    (Compound 1009),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1010),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,5-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1013),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1051),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[2.4]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1061),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2,3,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1065),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-1,2-dihydropyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S)-2-tert-butylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1097),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1098),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1117),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1121),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2,3,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1144),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1149),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,3,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1156),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1157),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methylene-1-piperidyl)pyridine-3-carboxamide    (Compound 1162),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(5R)-2,2,5-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1166),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R)-2-tert-butylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1170),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1180),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-3-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-1,2-dihydropyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-methyl-1-piperidyl]pyridine-3-carboxamide    (Compound 1193),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-(3-chlorophenyl)ethyl-methyl-amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1205),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3S,5S)-3,5-dimethyl-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1210),-   N-[(6-amino-2-pyridyl)sulfonyl[-2-(2-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1218),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-5-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1222),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(5S)-2,2,5-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1241),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1258),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-phenylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1260),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(8-azaspiro[3.5]nonan-8-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1264),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylmorpholin-4-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1267),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1279),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1289),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[3.5]nonan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1303),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1304),-   2-(2,3,4,4a,5,6,7,7a-octahydrocyclopenta[b]pyridin-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1313),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-3-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1319)    N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[2.4]heptan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1333),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3R,5S)-3,5-dimethyl-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 371),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-piperidyl)pyridine-3-carboxamide    (Compound 380),-   2-(3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[b]pyrrol-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 383),-   methyl    (2S)-143-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyridyl]pyrrolidine-2-carboxylate    (Compound 385),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 398),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-methyl-1-piperidyl]pyridine-3-carboxamide    (Compound 408),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(azepan-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 418),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[3-(methoxymethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 419),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 420),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 421),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(8-oxa-4-azaspiro[4.4]nonan-4-yl)pyridine-3-carboxamide    (Compound 424),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 425),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-phenylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 447),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dihydropyrrol-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 453),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 458),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 473),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 479),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-4-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 488),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]pyridine-3-carboxamide    (Compound 490),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2-(1,1-dimethylpropyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 493),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,5-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 496),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-cyclopropylethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 516),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[3.3]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 527),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethyl-3-methyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 530),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 547),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 555),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 560),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,4-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 575),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,5S)-3-azabicyclo[3.2.1]octan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 581),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 587),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyrrolidin-1-yl-pyridine-3-carboxamide    (Compound 592),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopropylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 593),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 609),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-tert-butylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 611),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 613),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-ethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 615),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 651),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-cyclopropyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 655),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 657),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-(2-pyridyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 659),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 663),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 678),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-azabicyclo[2.2.1]heptan-3-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 680),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclobutyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 683),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 684),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 694),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethyl-3-phenyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 711),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 719),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 720),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 735),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 751),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 772),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethyl-3-(trifluoromethyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 780),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 837),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(8-azaspiro[3.4]octan-8-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 845),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 850),-   2-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 857),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 859),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(propyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 881),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 887),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-azabicyclo[3.1.0]hexan-4-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 906),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1S,4R)-3-azabicyclo[2.2.1]heptan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 924),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(9-azaspiro[4.4]nonan-9-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 926),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 931),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,5S)-8-azabicyclo[3.2.1]octan-8-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 934),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[2.5]octan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 953),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 969),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[2.5]octan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 973),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 991),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1004),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1-methylcyclopropyl)methyl]amino]pyridine-3-carboxamide    (Compound 1009),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1010),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,5-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1013),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1051),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[2.4]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1061),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2,3,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1065),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-1,2-dihydropyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S)-2-tert-butylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1097),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1098),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1117),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1121),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2,3,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1144),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1149),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,3,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1156),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1157),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methylene-1-piperidyl)pyridine-3-carboxamide    (Compound 1162),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(5R)-2,2,5-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1166),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R)-2-tert-butylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1170),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1180),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-3-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-1,2-dihydropyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-methyl-1-piperidyl]pyridine-3-carboxamide    (Compound 1193),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-(3-chlorophenyl)ethyl-methyl-amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1205),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3S,5S)-3,5-dimethyl-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1210),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1218),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-5-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1222),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(5S)-2,2,5-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1241),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1258),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-phenylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1260),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(8-azaspiro[3.5]nonan-8-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1264),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylmorpholin-4-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1267),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1279),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1289),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[3.5]nonan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1303),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1304),-   2-(2,3,4,4a,5,6,7,7a-octahydrocyclopenta[b]pyridin-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1313),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-3-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1319),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-methyl-1-piperidyl)-6-(p-tolyl)pyridine-3-carboxamide    (Compound 802),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methoxy-5-methyl-3-pyridyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 863),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxyphenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 910),-   6-(3-fluoro-5-isopropoxy-phenyl)-2-(4-methyl-1-piperidyl)-N-(1H-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide    (Compound 1042),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[2.4]heptan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1333),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3R,58)-3,5-dimethyl-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 371),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy    -phenyl)-2-(1-piperidyl)pyridine-3-carboxamide (Compound 380),-   2-(3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[b]pyrrol-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 383),-   methyl    (2S)-1-[3-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyridyl]pyrrolidine-2-carboxylate    (Compound 385),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 398),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-methyl-1-piperidyl]pyridine-3-carboxamide    (Compound 408),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(azepan-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 418),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[3-(methoxymethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 419),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 420),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 421),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(8-oxa-4-azaspiro[4.4]nonan-4-yl)pyridine-3-carboxamide    (Compound 424),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy    -phenyl)-2-(2-methyl-1-piperidyl)pyridine-3-carboxamide (Compound    425),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-phenylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 447),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dihydropyrrol-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 453),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 458),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 473),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 479),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-4-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 488),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]pyridine-3-carboxamide    (Compound 490),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2-(1,1-dimethylpropyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 493),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,5-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 496),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-cyclopropylethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 516),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[3.3]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 527),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethyl-3-methyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 530),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 547),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 555),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 560),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,4-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 575),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,5S)-3-azabicyclo[3.2.1]octan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 581),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 587),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyrrolidin-1-yl-pyridine-3-carboxamide    (Compound 592),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopropylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 593),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 609),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-tert-butylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 611),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 613),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-ethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 615),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 651),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-cyclopropyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 655),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 657),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-(2-pyridyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 659),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 663),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 678),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-azabicyclo[2.2.1]heptan-3-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 680),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclobutyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 683),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 684),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 694),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethyl-3-phenyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 711),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 719),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 720),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 735),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 751),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 772),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethyl-3-(trifluoromethyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 780),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 837),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(8-azaspiro[3.4]octan-8-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 845),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 850),-   2-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 857),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 859),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(propyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 881),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 887),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-azabicyclo[3.1.0]hexan-4-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 906),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1S,4R)-3-azabicyclo[2.2.1]heptan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 924),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(9-azaspiro[4.4]nonan-9-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 926),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 931),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,5S)-8-azabicyclo[3.2.1]octan-8-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 934),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[2.5]octan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 953),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 969),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[2.5]octan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 973),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 991),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1004),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1-methylcyclopropyl)methyl]amino]pyridine-3-carboxamide    (Compound 1009),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1010),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,5-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1013),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1051),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[2.4]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1061),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2,3,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1065),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-1,2-dihydropyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S)-2-tert-butylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1097),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-isopropyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1098),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1117),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1121),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2,3,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1144),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1149),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,3,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1156),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclopropylmethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1157),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methylene-1-piperidyl)pyridine-3-carboxamide    (Compound 1162),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(5R)-2,2,5-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1166),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R)-2-tert-butylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1170),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1180),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-3-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-1,2-dihydropyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-methyl-1-piperidyl]pyridine-3-carboxamide    (Compound 1193),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-(3-chlorophenyl)ethyl-methyl-amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1205),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3S,5S)-3,5-dimethyl-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1210),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1218),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-5-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1222),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(5S)-2,2,5-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1241),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1258),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-phenylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1260),-   N-[(6-amino-2-pyridyl)sulfonyl)-2-(8-azaspiro[3.5]nonan-8-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1264),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylmorpholin-4-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1267),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1279),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1289),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[3.5]nonan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1303),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1304),-   2-(2,3,4,4a,5,6,7,7a-octahydrocyclopenta[b]pyridin-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1313),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-3-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1319),-   2-(2,5-dimethyl-3-phenyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1348),-   2-[(3,3-difluorocyclobutyl)methylamino]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 393),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 415),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-[4-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 426),-   2-(3-ethynyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 431),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 442),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-isopropyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 498),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-spiro[1H-isobenzofuran-3,4′-piperidine]-1′-yl-pyridine-3-carboxamide    (Compound 506),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-oxa-8-azaspiro[3.5]nonan-8-yl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 519),-   2-(3,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 528),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-isopropyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 553),-   2-[4-(cyanomethyl)-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 556),-   2-(3,3-difluoropyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 565),-   2-(2-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 591),-   2-[(3R,5S)-3,5-dimethyl-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 642),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-methyl-1-piperidyl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 668),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-[3-(2-pyridyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 677),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-phenylpyrrolidin-1-yl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 716),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-fluoro-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 728),-   2-(azepan-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 734),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-indolin-1-yl-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 739),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxy-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 749),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 756),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methoxy-4-methyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 774),-   2-(3-ethoxy-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 843),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-fluoro-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 878),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 904),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-[3-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 907),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-phenyl-1-piperidyl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 912),-   2-[(3R,5R)-3,5-dimethyl-1-piperidyl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 942),-   2-(7-azaspiro[3.5]nonan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 944),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,3,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 952),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(methoxymethyl)-1-piperidyl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 975),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-isoindolin-2-yl-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 981),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,2,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 997),-   2-(3,3-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1005),-   2-(4,4-difluoro-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1006),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-[3-(methoxymethyl)-1-piperidyl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1028),-   2-(4-ethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1030),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1041),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-phenylpyrrolidin-1-yl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1060),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1083),-   2-[4-(cyclopropylmethoxy)-1-piperidyl[-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1088),-   2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1110),-   2-(2,6-dimethylmorpholin-4-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1119),-   2-(6-azaspiro[2.5]octan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1127),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylpyrrolidin-1-yl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1142),-   2-(4-ethoxy-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1155),-   2-(2,3-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1169),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-(3,3,4-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1174),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1176),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methoxy-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1245),-   2-(2-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1257),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-[[3-(trifluoromethyl)cyclohexyl]amino]pyridine-3-carboxamide    (Compound 1281),-   2-(8-azaspiro[3.4]octan-8-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1282),-   6-(6-isopropoxy-3-pyridyl)-N-(1H-pyrazol-5-ylsulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1352),-   2-(3-cyclopropyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1286),-   2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1302),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-phenyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1315),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isopropoxy-phenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 600),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isopropoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 972),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isopropoxy-phenyl)pyridine-3-carboxamide    (Compound 1123),-   N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-(1-piperidyl)pyridine-3-carboxamide    (Compound 753),-   N-(4-aminophenyl)sulfonyl-2-(benzylamino)-6-tert-butyl-pyridine-3-carboxamide    (Compound 1064),-   N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-(4-methoxy-1-piperidyl)pyridine-3-carboxamide    (Compound 1298),-   N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-[(4-methyltetrahydropyran-4-yl)methylamino]pyridine-3-carboxamide    (Compound 752),-   N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1037),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 794),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3,3-dimethylbutoxy)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1008),-   N-[(6-amino]-2-pyridyl)sulfonyl]-6-tert-butyl-2-[4-(methoxymethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 986),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3,5-dimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 617),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[4-(1-hydroxy-1-methyl-ethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 1038),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(4-methoxy-1-piperidyl)pyridine-3-carboxamide    (Compound 1164),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(4-ethoxy-1-piperidyl)pyridine-3-carboxamide    (Compound 1200),-   2-[(4-methyltetrahydropyran-4-yl)methylamino]-6-(p-tolyl)-N-(1H-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide    (Compound 879)-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4-methyltetrahydropyran-4-yl)methylamino]-6-(p-tolyl)pyridine-3-carboxamide    (Compound 1196),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 373),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(3S)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 1261),-   N-[(2-amino-3-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1316),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1240),-   N-[(2-amino-3-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1159),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-methyl-2-[(3S)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 532),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(3R)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 626),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1074),-   6-(6-isopropoxy-3-pyridyl)-2-[(3R)-3-phenyl-1-piperidyl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 741),-   6-(6-isopropoxy-3-pyridyl)-2-[(3S)-3-phenyl-1-piperidyl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 776),-   2-[(3R,5S)-3,5-dimethyl-1-piperidyl]-6-(6-isopropoxy-3-pyridyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 446),-   2-[(3R,5R)-3,5-dimethyl-1-piperidyl]-6-(6-isopropoxy-3-pyridyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 990),-   6-(6-isopropoxy-3-pyridyl)-2-(4-methyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 534),-   N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-azabicyclo[2.2.2]octan-3-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1657),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(3S)-2,2-dideuterio-3,5,5-trimethyl-pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1400),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-azabicyclo[3.1.1]heptan-3-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1529),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,5,5-trimethylmorpholin-4-yl)pyridine-3-carboxamide    (Compound 1548),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(5,7-dimethylindolin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1572),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4R)-4-ethyl-2,2-dimethyl-pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1611),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-4-ethyl-2,2-dimethyl-pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1612),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,5,5-tetramethylmorpholin-4-yl)pyridine-3-carboxamide    (Compound 1675),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,5-diisopropylpyrazol-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1387),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-difluoroazetidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2155),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylazetidin-1-yl)pyridine-3-carboxamide    (Compound 1840),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-fluoroazetidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2128),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6,6-dimethyl-7-azaspiro[3.4]octan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2589),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(5-azabicyclo[4.1.0]heptan-5-y0-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2376),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(6-methyl-3-azabicyclo[3.1.1]heptan-3-yl)pyridine-3-carboxamide    (Compound 2224),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[[1-(2-hydroxy-2-methyl-propyl)cyclopropyl]methylamino]pyridine-3-carboxamide    (Compound 1723),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamide    (Compound 2552),-   N1(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylazetidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1928),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1′-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2532) (Isomer 1) (Compound 2178) (Isomer 2)    (Compound 2062) (Isomer 3) (Compound 1863) (Isomer 4),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2451) (Isomer 1) (Compound 1993) (Isomer 2)    (Compound 1864) (Isomer 3) (Compound 1855) (Isomer 4),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-hydroxy-1-piperidyl)pyridine-3-carboxamide    (Compound 2323),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[cyclohexylmethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2289),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,5-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1995),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2201),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-BLAHyl-pyridine-3-carboxamide    (Compound 1821),-   N-[(6-amine-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(5-methyl-7-azaspiro[2.4]heptan-7-yl)pyridine-3-carboxamide    (Compound 1754),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-tert-butyl-2,2-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2538),-   tert-butyl    (2R)-1-[3-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyridyl]pyrrolidine-2-carboxylate    (Compound 2216),-   tert-butyl    (2S)-1-[3-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyridyl]pyrrolidine-2-carboxylate    (Compound 2204),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethyl-1-piperidyl)pyridine-3-carboxamide    (Compound 2581),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-difluoro-2,2-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2631),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(5,5-dimethyl-6-azaspiro[2.4]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1746),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methylazetidin-1-yl)pyridine-3-carboxamide    (Compound 2117),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethyl-4-(trifluoromethyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1788),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-methyl-5-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide    (Compound 1835),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,5-dimethylazepan-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2479),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-dimethylazepan-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2171),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylazepan-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1901),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(cyclohexylmethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2375),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(1-piperidyl)pyridine-3-carboxamide    (Compound 571),-   and-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 361).

PREPARATION 40:2-(Benzenesulfonyl)-3-[5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazol-3-yl]-3-oxo-propanoate(Compound 4)

5-tert-Butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxylic acid(100 mg, 0.35 mmol) was dissolved in thionyl chloride (26 μL, 0.35 mmol)and a drop of N,N-dimethylformamide was added. The mixture was stirredfor 1 h and evaporated to give the acid chloride.

A mixture of the acid chloride (40 mg, 0.13 mmol), methyl2-(benzenesulfonyl)acetate (28 mg, 0.13 mmol) and NaH (60%, 5.3 mg, 0.13mmol) in N,N-dimethylformamide (1 mL) were stirred at room temperaturefor 15 min. The mixture was filtered and purified by reverse-phasepreparatory-HPLC (10-99% CH₃CN/H₂O, HCl modifier) to give2-(benzenesulfonyl)-3-[5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazol-3-yl]-3-oxo-proparioate(Compound 4). ESI-MS m/z calc, 482.6, found 483.4 (M+1)⁺; Retentiontime: 2.41 min (3 min run).

PREPARATION 41:6-(3-isoButoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125) Step 1:6-chloro-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

6-Chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (5.09 g,17.5 mmol) was dissolved in thionyl chloride (6.36 mL, 87.3 mmol),CH₂Cl₂ (1 mL) and N,N-dimethylformamide (one drop). The reaction mixturewas stirred for 30 min before it was concentrated to give the acidchloride.

The acid chloride was dissolved in CH₂Cl₂ (1 mL) and was added tosolution of 2-methoxypyridine-3-sulfonamide (3.69 g, 17.5 mmol) inCH₂Cl₂ (1 mL) containing triethylamine (7.30 mL, 52.4 mmol) at 0° C. Themixture was allowed to stir at room temperature overnight before it wasdiluted with CH₂Cl₂ and washed with 1N HCl, saturated NaHCO₃, and thenbrine. The organic layer was dried over sodium sulfate and concentratedto give6-chloro-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(6.20 g, 77%) ESI-MS m/z calc. 461.1, found 462.2 (M+1)⁺; Retentiontime: 0.74 min (1 min run).

Step 2:6-chloro-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

A mixture of6-chloro-N-[(2-methoxy-3-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(500 mg, 1.08 mmol), 1,4-dioxane (10 mL) and HCl (2.71 mL of 4 M, 10.8mmol) was heated at 90° C. for 3.5 h. The volatiles were removed to give6-chloro-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(372 mg, 77%) ESI-MS m/z calc. 447.1, found 448.2 (M+1)⁺; Retentiontime: 0.63 min (1 min run).

Step 3:6-(3-isoButoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125)

A mixture of6-chloro-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(56 mmol, 0.10 mmol), 3-isobutoxyphenyl boronic acid (39 mg, 0.2 mmol),Pd(PPh₃)₄ (7 mg, 0.006 mmol), K₂CO₃ (2 M, 200 μL, 0.4 mmol) andN,N-dimethylformamide (1 mL) was flushed with nitrogen and sealed. Themixture was then stirred at 80° C. for 18 h. The resultant solid wasdiluted with water and filtered. Then solid was taken up in ethylacetate, filtered and concentrated to give6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl[-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 125). ESI-MS m/z calc. 561.2, found 562.2 (M+1)⁺; Retentiontime: 2.23 min (3 min run).

The following compound can be synthesized using the procedures describedherein:

-   6-(4-chloro-3-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 72),-   2-(2,4-dimethylphenoxy)-6-(4-ethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 517),-   6-(4-chloro-3-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 136),-   6-(2,5-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 545),-   6-(3,4-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 546),-   6-(2-fluoro-5-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 552),-   6-(4-fluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 561),-   6-(4,4-dimethylcyclohexen-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 573),-   6-(4-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 579),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-indol-4-ylsulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 549),-   2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-hydroxyphenyl)sulfonyl-pyridine-3-carboxamide    (Compound 1309),-   2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-indol-4-ylsulfonyl)pyridine-3-carboxamide    (Compound 1323),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-methoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 726),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1471),-   isopropyl    4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(2,4,6-trimethylphenoxy)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate    (Compound 1366),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethylcyclohexen-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1370),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1389),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2-dimethylprop-1-enyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1390),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluouromethyl)cyclohexen-1-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    trimethylphenoxy)pyridine-3-carboxamide (Compound 1402),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4,7,7-trimethyl-3-bicyclo[2.2.1]hept-2-enyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1410),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-dihydrofuran-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1412),-   ethyl    4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(2,4,6-trimethylphenoxy)-2-pyridyl]cyclohex-3-ene-1-carboxylate    (Compound 1432),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,4-dioxaspiro[4.5]dec-8-en-9-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1437),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6,6-dimethyl-2,3-dihydropyran-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1460),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(cyclohepten-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1513),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-bicyclo[2.2.1]hept-2-enyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1518),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5,5-dimethyl-3-oxo-cyclohexen-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1528),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5,5-dimethyl-2-oxo-cyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1427),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-cycloheptyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1376),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,2-dimethyltetrahydropyran-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1466),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethylcyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1475),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2-dimethylpropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1486),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,3-dimethyl-5-oxo-cyclohexyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1492),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1517),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1519),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylcyclohexen-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1630),-   6-(4-acetylcyclohexyl)-N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1631),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,7,7-trimethylnorbornan-2-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1650),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(2-methylpropanoyl)-3,6-dihydro-2H-pyridin-4-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1540),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,4-dioxaspiro    [4.5]dec-8-en-8-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1558),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,3-dimethyl-6-oxo-cyclohexen-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1598),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,2,5,5-tetramethyl-3-furyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1609),-   6-(4-acetylcyclohexen-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1615),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2,3,6-tetrahydropyridin-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1643),-   6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1649),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-isopropoxy-5-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1674),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1488),-   N-[(6-amino-2-pyridyl)sulfonyl]-643-ethoxy-5-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1569),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isopropoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1671),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1646),-   N-(2-azidophenyl)sulfonyl-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide,-   N-(2-azidophenyl)sulfonyl-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-cyclohexyl-2-[(2S,5R)-2,5-dimethylpyrroliclin-1-yl]pyridine-3-carboxamide    (Compound 704),-   6-(4-fluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 608),-   6-(4-fluoro-3-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 624),-   6-(3-fluoro-5-isopropoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 645),-   6-(3-fluoro-5-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 652),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 654),-   6-(2-fluoro-5-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 762),-   6-(2-fluoro-3-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 804),-   6-(3,5-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 815),-   6-(4-ethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 831),-   6-(3-ethoxy-5-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 835),-   6-(2-fluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 839),-   6-(2-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 877),-   6-(cyclohexen-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 882),-   6-(2,5-dimethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 888),-   6-(3-ethoxy-4-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 917),-   6-(6-methoxy-5-methyl-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 930),-   6-(6-ethoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 932),-   6-(1-methylindol-6-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 936),-   6-(2-chloro-3-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 955),-   6-(3-butoxy-2-chloro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 964),-   6-(4-methoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 980),-   6-(3-chloro-4-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 999),-   6-(4-isopropylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1002),-   6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1007),-   6-(3-fluoro-4-propoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1022),-   6-(4-methylcyclohexen-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1052),-   6-(4-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1079),-   6-(3-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1095),-   6-[3-(cyclopropylmethoxy)phenyl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1105),-   2-(2,4-dimethylphenoxy)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(p-tolyl)pyridine-3-carboxamide    (Compound 1129),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(3-propoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1143),-   6-(5-fluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1151),-   6-(4-ethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1179),-   6-(4-butoxy-3-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1187),-   6-(3-isopropoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1188),-   6-(2-chloro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1201),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(4-propoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1202),-   6-(2,3-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1296),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(p-tolyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1300),-   6-(5-ethoxy-2-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1301),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 169),-   2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(p-tolyl)pyridine-3-carboxamide    (Compound 392),-   6-(6-isopropoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 403),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isopropoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 487),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 492),-   6-(6-isopropoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 497),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 511),-   6-[3-(cyclopropylmethoxy)-5-fluoro-phenyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 541),-   6-[3-(2,2-dimethylpropoxy)-5-fluoro-phenyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 572),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isopropylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 589),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 605),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-phenyl-pyridine-3-carboxamide    (Compound 660),-   6-[3-(cyclopropylmethoxy)-5-fluoro-phenyl]-2-(4-methyl-1-piperidyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 664),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isopentyloxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 688),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 721),-   6-(3-fluoro-5-isopropoxy-phenyl)-2-(4-methyl-1-piperidyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 737),-   6-(4-chlorophenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 760),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 770),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-methoxy-2-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 781),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 891),-   6-(4-chloro-3-isobutoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 902),-   6-[3-(cyclobutylmethoxy)-5-fluoro-phenyl]-2-[(2S,5R)-2,5-dimethylpyrroliclin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 922),-   6-(4-chloro-3-isobutoxy-phenyl)-2-(4-methyl-1-piperidyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 941),-   6-(3-isobutoxyphenyl)-2-(4-methyl-1-piperidyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 958),-   6-(4-chloro-3-isopropoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 1001),-   6-(4-isobutoxyphenyl)-2-(4-methyl-1-piperidyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 1017),-   2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-ethoxy-5-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 1096),-   8,8-dimethyl-2-(4-methyl-1-piperidyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 1195),-   6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 1293),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(3S)-3-phenyl-1-piperidyl]pyridine-3-carboxamide    (Compound 481),-   6-(2-methoxy-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2530),-   6-(3-ethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2235),-   6-(4-methoxy-2-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2469),-   6-(4-ethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2207),-   6-(2-methoxy-3-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1880),-   6-isobutyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2467),-   6-(3-methoxy-4-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2440),-   6-(3-isopropoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2549),-   6-(4-isopropoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1774),-   6-(2-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2629),-   6-(3-fluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2219),-   6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2267),-   6-(2-fluoro-6-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2422),-   6-(4-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2153),-   6-(2-fluoro-3-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2222),-   6-(5-fluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1830),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[3-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1934),-   6-(2-fluoro-5-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2606),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[4-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2234),-   6-(4-fluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2356),-   6-(3-fluoro-5-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2527),-   N-[(2-oxo-1H-pyridin    -3-yl)sulfonyl]-6-[3-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2144),-   6-(2-fluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1858),-   6-(3-fluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1779),-   6-(4-fluoro-3-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1780),-   6-(2-naphthyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1803),-   6-(1-naphthyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2007),-   6-(2,4-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2037),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(2,3,5-trifluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1837),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(2,4,5-trifluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1981),-   6-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2516),-   6-(2-hydroxy-3-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2300),-   6-(3-ethoxy-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2512),-   6-(2,3-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2073),-   6-(2-hydroxy-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2174),-   6-(5-fluoro-2-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2067),-   6-(2-ethoxy-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2410),-   6-(4-methoxy-2,6-dimethyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2575),-   6-[3-(hydroxymethyl)-5-methoxy-phenyl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(45)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2247),-   6-(2,3-dimethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1786),-   6-(2,5-dimethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1752),-   6-(2-hydroxy-4-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2148),-   6-(3,5-dimethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1878),-   6-(2-ethoxy-5-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2051),-   6-(5-ethoxy-2-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2138),-   6-(3-ethoxy-2-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1802),-   6-(2-ethoxy-4-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1867),-   6-(3,5-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2626),-   6-(3-ethoxy-5-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2278),-   6-(3-ethoxy-4-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2459),-   6-(3,4-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2154),-   6-(4-methyl-1-naphthyl)-N-[(2-oxo-1H-pridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1811),-   6-(2-isopropylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2635),-   6-(4,5-difluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1904),-   6-(3,5-difluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2496),-   6-(2,3-difluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2567),-   6-(3,5-difluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1801),-   6-(3,4-difluoro-5-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1914),-   6-(2,5-difluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1913),-   6-(4-hydroxy-3,5-dimethyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2556),-   6-(1H-indol-5-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1982),-   6-(1H-indol-4-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2636),-   6-(6-ethoxy-4-methyl-2-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1745),-   6-(3-fluoro-4-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2084),-   6-(2-fluoro-4-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2000),-   6-(3-fluoro-2-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2491),-   6-(2-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1784),-   6-(3-fluoro-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2348),-   6-(2-fluoro-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1946),-   6-(3-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1791),-   6-(3,4-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2284),-   6-(4-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2028),-   6-(2,4-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2159),-   6-(2,3-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2162),-   6-(3,5-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2652),-   6-(2,5-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1954),-   6-(2-fluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2542),-   6-(2-isopropoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2541),-   6-(3-cyanophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2185),-   6-(3-fluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1925),-   6-(4-fluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1807),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[2-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1960),-   6-(2-methoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2454),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2315),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1710),-   6-(2,5-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1990),-   6-(o-tolyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2176),-   6-(4-fluoro-3-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2456),-   6-(5-fluoro-6-methoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2444),-   6-(6-methoxy-2-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2101),-   6-(2,6-dimethoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1853),-   6-(3-isopropylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2498),-   6-(4-isopropylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2483),-   6-(5-fluoro-2-hydroxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2295),-   6-(2-methoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2485),-   6-(2,3-dihydrobenzofuran-7-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2583),-   6-(4-methoxy-3-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2369),-   6-(2-ethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1848),-   6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-methyl-1-piperidyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 422), and-   6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 279).

PREPARATION 42:N-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 197) Step 1:8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carbonitrile

A mixture of2-chloro-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carbonitrile (1.00 g,4.51 mmol) and 4-methylpiperidine (4.29 mL, 36.3 mmol) was stirred at100° C. for 1 h. The reaction mixture was diluted with water and wasextracted with ethyl acetate (3×). The combined extracts were washedwith water, dried over sodium sulfate, and evaporated. The residue waspurified by silica gel chromatography with 0-5% ethyl acetate in hexanesto give8,8-dimethyl-2-(4-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile(1.00 g, 78%) as a colorless oil. ESI-MS m/z calc. 283.2, found 284.3(M+1)⁺; Retention time: 0.94 min (1 min run).

Step 2:8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydra-5H-quinoline-3-carboxylicacid

A solution of8,8-dimethyl-2-(4-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile(0.80 g, 2.8 mmol) and KOH (1.6 g, 28 mmol) in ethanol (5.6 mL) washeated at reflux for 4 d. The reaction mixture was neutralized with 1 MHCl, and the solids were filtered, washed with water, and dried undervacuum to give8,8-dimethyl-2-(4-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxylicacid (0.71 g, 83%) as a tan solid. ESI-MS m/z calc. 302.2, found 303.3(M+1)⁺; Retention time: 0.58 min (1 min run).

Step 3:N-(3-chloropyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide

A solution of8,8-dimethyl-2-(4-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxylicacid (0.11 g, 0.36 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (170 mg, 0.44 mmol) and sodium carbonate (77mg, 0.73 mmol) in N,N-dimethylformamide (1.8 mL) was stirred for 5 minbefore 3-chloropyrazine-2-sulfonamide (110 mg, 0.55 mmol) was added. Thereaction mixture was stirred for 20 h, filtered, and subjected topreparatory-HPLC (1-99% CH₃CN/water) to giveN-(3-chloropyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(75mg, 43%). ESI-MS m./z, calc. 477.2, found 478.3 (M+1)⁺; Retentiontime: 0.65 min (1 min run).

Step 4:N.(3-Aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide

N-(3-Chloropyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(35 mg, 0.073 mmol) and ammonium hydroxide (1 mL, 26 mmol) was heated ina sealed vial in an microwave reactor at 120° C. for 20 min. Thereaction mixture was concentrated, the residue was taken up in DMSO andsubjected to preparatory-HPLC (1-99% CH₃CN/water) to giveN-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide(Compound 197) (8.7 mg, 26%). ESI-MS m/z calc. 458.2, found 459.3(M+1)⁺; Retention time: 1.67 min (3 min run).

The following compound can be synthesized using the procedures describedherein:

-   N-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(p-tolyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 707),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(4-ethoxyphenyl)-2-(p-tolyl)pyridine-3-carboxamide    (Compound 819),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(3-fluoro-5-isopropoxy-phenyl)-2-(p-tolyl)pyridine-3-carboxamide    (Compound 1351),-   N-(3-aminopyrazin-2-yl)sulfonyl-2,6-bis(p-tolyl)pyridine-3-carboxamide    (Compound 820),-   N-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(p-tolyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 707),-   N-(3-aminopyrazin-2-yl)sulfonyl-2-(2,4-dimethylphenoxy)-6-(4-ethoxyphenyl)pyridine-3-carboxamide    (Compound 434),-   N-[(6-amino-3-pyridyl)sulfonyl]-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 702),-   N-(6-aminopyrazin-2-yl)sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 586),-   N-(3-aminopyrazin-2-yl)sulfonyl-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 1223),-   N-(3-aminopyrazin-2-yl)sulfonyl-2-(2,4-dimethylphenoxy)-8,8-dimethyl-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 1239),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1208),-   N-(3-aminopyrazin-2-yl)sulfonyl-2-(2,4-dimethylphenoxy)-6-(3-fluoro-5-isopropoxy-phenyl)pyridine-3-carboxamide    (Compound 559),-   N-(3-aminopyrazin-2-yl)sulfonyl-2-(2,4-dimethylphenoxy)-6-(p-tolyl)pyridine-3-carboxamide    (Compound 607),-   N-(3-aminopyrazin-2-yl)sulfonyl-2-(2,4-dimethylphenoxy)-6-(1-isobutylpyrazol-4-yl)pyridine-3-carboxamide    (Compound 713),-   N-(3-aminopyrazin-2-yl)sulfonyl-2-(2,4-dimethylphenoxy)-6-(6-methoxy-5-methyl-3-pyridyl)pyridine-3-carboxamide    (Compound 893),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(3-fluoro-5-isopropoxy-phenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 989),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(4-ethoxyphenyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1019),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(p-tolyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1047),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(1-isobutylpyrazol-4-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1103),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(6-methoxy-5-methyl-3-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1249),-   N-(3-aminopyrazin-2-yl)sulfonyl-2-[(4-methyltetrahydropyran-4-yl)methylamino]-6-(p-tolyl)pyridine-3-carboxamide    (Compound 1066),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(4-ethoxyphenyl)-2-[(4-methyltetrahydropyran-4-yl)methylamino]pyridine-3-carboxamide    (Compound 1203),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(1-isobutylpyrazol-4-yl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1288),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(6-methoxy-5-methyl-3-pyridyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1191),-   N-(3-aminopyrazin-2-yl)sulfonyl-2-(4-methyl-1-piperidyl)-6-(p-tolyl)pyridine-3-carboxamide    (Compound 1084),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(3-fluoro-5-isopropoxy-phenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 699),-   N-(3-aminopyrazin-2-yl)sulfonyl-6-(4-ethoxyphenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 507),-   8,8-dimethyl-2-(4-methyl-1-piperidyl)-N-(1H-pyrazol-5-ylsulfonyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 800),-   N-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(4-methyl-1-piperidyl)-6,7-dihydro-5H-quinoline-3-carboxamide    (Compound 750), and-   N-[(2-amino-3-pyridyl)sulfonyl]-6-tert-butyl-2-(p-tolyl)pyridine-3-carboxamide    (Compound 636).

PREPARATION 43:N-[(3-Aminophenyl)sulfonimidoyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 292) Step 1: sodium 3-nitrobenzene-1-sulfinate

To a colorless solution of sodium sulfite (6.26 g, 49.6 mmol) in water(50 mL) at 80° C., were added 3-nitrobenzenesulfonyl chloride (5.00 g,22.6 mmol) and sodium carbonate (4.30 g, 40.6 mmol). The reactionmixture was stirred at 80° C. for 2 h. The reaction mixture wasconcentrated under reduced pressure. The residue was suspended inethanol (45 mL) and heated at 80° C. for 1 H. The reaction mixture wascooled to room temperature and filtered to remove most of the salts. Thefiltrate was concentrated under reduced pressure to give sodium3-nitrobenzene-1-sulfinate (4.20 g, 89% yield, containing some salts).¹H NMR (300 MHz, CDCl₃) δ 7.68 (t, J=7.8 Hz, 1H), 8.02 (dt, J=7.7, 1.4Hz, 1H), 8.21-8,28 (m, 1H), 8.47-8.51 (m, 1H). [M+H]⁺=188.0.

Step 2: methyl 3-nitrobenzene-1-sulfinate

Thionyl chloride (3.27 mL, 45.0 mmol) was added to a solution of sodium3-nitrobenzene-1-sulfinate (3.14 g, 15.0 mmol) in dichloromethane (21mL) at 0° C. After 20 minutes at 0° C., the reaction mixture was allowedto warm to room temperature and stirred for 3 h. The reaction mixturewas concentrated and dried under vacuum to give a residue (3.08 g, 15mmol). To the residue was added dichloromethane (5 mL) and methanol (100mL) at 0° C. After 10 minutes at this temperature, triethylamine (6.27mL, 45 0 mmol) was added and the mixture was stirred at room temperatureovernight. The mixture was concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (50 mL), washed with water (25mL), brine (25 mL), dried over anhydrous sodium sulfate and concentratedto give methyl 3-nitrobenzene-1-sulfinate (1.40 g, 46% yield). ¹H NMR(300 MHz, CDCl₃) δ 3.52 (s, 3H), 7.71 (t, J=7.8 Hz, 1H), 7.98 (dt,J=7.7, 1.4 Hz, 1H), 8.21-8.28 (m, 1H), 8.47-8.51 (m, 1H). [M+H]⁺=202.0.

Step 3:6-tert-butyl-N-(3-nitrobenzenesulfinyl)-2-(2,4,6-trimethylphenoxy)-pyridine-3-carboxamide

To a solution methyl 3-nitrobenzene-1-sulfinate (1.35 g, 6.70 mmol) indimethylformamide (8.0 mL) was added methyl 3-nitrobenzene-1-sulfinate(697 mg, 2.68 mmol), followed by cesium carbonate (2.18 g, 6.69 mmol).The mixture was stirred overnight at 60° C. The mixture was diluted withethyl acetate (60 mL), washed with water (30 mL), brine (30 mL), driedover anhydrous sodium sulfate, filtered, and concentrated. The crudematerial was purified by chromatography on silica gel, eluting with10-20% ethyl acetate in heptane to give6-tert-butyl-N-(3-nitrobenzenesulfinyl)-2-(2,4,6-trimethylphenoxy)-pyridine-3-carboxamide(725 mg, impure). This material was used in the next step withoutfurther purification. [M+H⁺=482.1.

Step 4:6-tert-butyl-N-[imino(3-nitrophenyl)oxo-λ⁶-sulfanyl]-2-(2,4,6-trimethyl-phenoxy)pyridine-3-carboxamide

To a solution of6-tert-butyl-N-(3-nitrobenzenesulfinyl)-2-(2,4,6-trimethylphenoxy)-pyridine-3-carboxamide(724 mg, 1.50 mmol) and potassium tert-butoxide (337 mg, 3.00 mmol) inacetonitrile (7.5 mL) was added hexamethyldisilazane (0.94 mL, 4.5mmol), followed by N-chlorosuccinimide (0.60 g, 4.5 mmol). Afterstirring for 15 min, additional hexamethyldisilazane (0.94 mL, 4.5mmol), followed by N-chlorosuccinimide (0.60 g, 4.5 mmol) were added.The mixture was stirred until TLC indicated completion. The mixture wasconcentrated and the residue was purified by flash chromatography,eluting with 20-50% ethyl acetate in heptane to give6-tert-butyl-N-[imino(3-nitrophenyl)oxo-λ⁶-sulfanyl]-2-(2,4,6-trimethyl-phenoxy)pyridine-3-carboxamide(95 mg, 3% over two steps). ¹H NMR (300 MHz, CDCl₃) δ 1.07 (s, 9H), 2.03(s, 6H), 2.30 (s, 3H), 6.87 (s, 2H), 6.98 (d, J=8.0 Hz, 1H), 7.74 (t,J=8.2 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.41-8.53 (m, 2H), 8.95 (s, 1H).[M+H]⁺=497.2.

Step 5:N-[(3-aminophenyl)sulfonimidoyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

To a solution of6-tert-butyl-N-[imino(3-nitrophenyl)oxo-λ⁶-sulfanyl]-2-(2,4,6-trimethyl-phenoxy)pyridine-3-carboxamide(90 mg, 0.18 mmol) in methanol (2.6 mL) was added 10% Pd/C (19 mg, 0.018mmol) and the mixture was stirred at room temperature for 3 h. Thesolvent was removed under vacuum and the crude material was purified byflash chromatography eluting with 20-50% ethyl acetate/heptane to giveN-[(3-aminophenyl)sulfonimidoyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(52 mg, 62% yield). ¹H NMR (300 MHz, CDCl₃) δ 1.01 (s, 91-1), 1.92 (s,6H), 2.22 (s, 3H), 5.57 (br. s, 2H), 6.73 (d, J=8.1 Hz, 111), 6.85 (s,2H), 6.97-7.07 (m, 2H), 7.11-7.20 (m, 2H), 7.56 (br. s, 21-1), 8.09 (d,J=7.8 Hz, 1H). [M+H]⁺=467.2.

Step 6:N-[(3-aminophenyl)sulfonimidoyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 19 and Compound 53)

N-[(3-Aminophenyl)sulfonimidoyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(30 mg, 0.064 mmol) was taken up in methanol (1.8 mL) and CH₂Cl₂ (0.4mL). The solution was subjected to chiral SFC (30 μL injections; column:Chiralpak AS-H (250×10 mm), 5 μm; mobile phase: 25% methanol w/20 mMNH₃, 75% CO₂; flow: 10 mL/min) to giveN-[(3-aminophenyl)sulfonimidoyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)-pyridine-3-carboxamide[peak 1, enantiomer 1, 97.9% ee, ¹H NMR (400 MHz, Chloroform-d) δ 8.27(d, J=7.9 Hz, 1H), 7.49-7.36 (m, 2H), 7.22 (t, J=7.9 Hz, 1H), 6.92 (d,J=7.8 Hz, 1H), 6.87-6.75 (m, 3H), 3.89 (s, 2H), 2.29 (s, 3H), 2.02 (s,6H), 1.06 (s, 9H)] andN-[(3-aminophenyl)sulfonimidoyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide[peak 2, enantiomer 2, 96% ee, ¹H NMR (400 MHz, Chloroform-d) δ 8.27 (d,J=7.9 Hz, 1H), 7.49-7.33 (m, 2H), 7.23 (t, J=7.9 Hz, 1H), 6.92 (d, J=7.9Hz, 1H), 6.88-6.74 (m, 3H), 3.89 (s, 2H), 2.29 (s, 3H), 2.02 (s, 6H),1.06 (s, 9H)].

The following compounds can be prepared using the procedures describedherein:

-   N-[S-(3-aminophenyl)-N-methyl-sulfonimidoyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 568),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[1-phenylethyl]pyrazole-3-carboxamide    can be separated to give    N-((3-aminophenyl)sulfonyl-5-tert-butyl-2-[(1S)-1-phenylethyl]pyrazole-3-carboxamide    (Compound 138) and    N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(1R)-1-phenylethyl]pyrazole-3-carboxamide    (Compound 540) using Chiralcel OJ-H (250×10 mm), 5 μm column;-   N-(3-aminophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    can be separated to give    (1,5)-N-(3-aminophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 126) (Compound 126) and    (1R)—N-(3-aminophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide    (Compound 310) using Chiralpak AD-H (250×10mm), 5 μm column.

PREPARATION 44:N-[(6-Amino-3-fluoro-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 226) Step 1: 2-(benzylthio)-3,6-difluoropyridine

To a solution of 2,3,6-trifluoropyridine (532 mg, 4.00 mmol) andphenylmethanethiol (470 μL, 4.00 mmol) in THF (20 mL) was added NaH(60%, 176 mg, 4.40 mmol) in portions. After 1 h, the mixture wasquenched with saturated aqueous ammonium chloride and extracted withethyl acetate (3×). The combined extracts were washed with water, driedover sodium sulfate, and evaporated. The residue was purified by silicagel chromatography with 0-20% ethyl acetate in hexanes to give2-(benzylthio)-3,6-difluoropyridine (0.63 g, 66%) as a colorless oil.ESI-MS m/z calc. 237.0, found 237.9 (M+1)⁺; Retention time: 0.72 min (1min run).

Step 2: 3,6-difluoropyridine-2-sulfonyl chloride

Chlorine was bubbled through a vigorously stirred solution of2-(benzylthio)-3,6-difluoropyridine (0.27 g, 1.1 mmol) in chloroform andwater for min, and the reaction mixture was stirred for 1 h. Chlorinewas bubbled through the mixture for another 15 min, and the reactionmixture was stirred for 2 h. The reaction mixture was quenched withsaturated aqueous sodium metabisulfite solution and extracted withdichloromethane (3×). The combined extracts were washed with water,dried over sodium sulfate, and evaporated to give crude3,6-difluoropyridine-2-sulfonyl chloride (50% pure, 0.49 g) as acolorless oil. ESI-MS m/z calc. 213.0, found 213.8 (M+1)⁺; Retentiontime: 0.47 min (1 min run).

Step 3: 3,6-difluoropyridine-2-sulfonamide

A solution of 5,6-difluoropyridine-2-sulfonyl chloride (0.35 g, 1.6mmol) in dioxane (4 mL) was cooled in an ice bath before ammonia (6.6 mLof 0.5 M in dioxane, 3.3 mmol) was added. The reaction was stirred for 3h and the solvent was evaporated. The residue was purified by silica gelchromatography with 0-50% ethyl acetate in hexanes to give3,6-difluoropyridine-2-sulfonamide (72 mg, 23%) as a colorless solid.ESI-MS m/z calc. 194.0, found 194.8 (M₊1)⁺; Retention time: 0.15 min (1min run).

Step 4:6-tert-butyl-N-[(3,6-difluoro-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

A solution of6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (107mg, 0.340 mmol), 3,6-difluoropyridine-2-sulfonamide (66 mg, 0.34 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (194 mg, 0.510 mmol) and sodium carbonate(72 mg, 0.68 mmol) in N,N-dimethylformamide (2 mL) was stirred at roomtemperature for 18 h. The reaction was diluted with water and extractedwith ethyl acetate (3×). The combined extracts were washed with water,dried over sodium sulfate, and evaporated. The residue was purified bysilica gel chromatography with 0-5% methanol in dichloromethane to give6-(tert-butyl)-N-((3,6-difluoropyridin-2-yl)sulfonyl)-2-(mesityloxy)nicotinamide(33 mg, 18%) as a colorless solid. ESI-MS m/z calc. 489.2, found 490.2(M+1)⁺; Retention time: 0.85 min (1 min run).

Step 5:N4(6-amino-3-fluoro-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

A mixture of6-tert-butyl-N-[(5,6-difluoro-2-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(15 mg, 0.028 mmol) and ammonium hydroxide (1.0 mL of 30% w/v, 8.6 mmol)was heated in a sealed vessel in a microwave reactor at 130° C. for 30min and 150° C. for 60 min. The solvent was evaporated and the residuewas subjected to preparatory-HPLC (30%-99% acetonitrile / water (5 mMHCl)) to giveN-[(6-amino-3-fluoro-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(0.7 mg, 5%). ESI-MS m/z calc. 486.2, found 487.3 (M+1)⁺; Retentiontime: 2.15 min (3 min run).

PREPARATION 45:(2S,4R)-N-[(6-Amino-2-pyridyl)sulfonyl]-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide(Compound 236) Step 1: (2S,4R)-4-phenylpyrrolidine-2-carboxylic acidtrifluoroacetic acid salt

(2S,4R)-1-(Boc)-4-Phenylpyrrolidine-2-carboxylic acid (1.01 g, 3.47mmol) was dissolved in trifluoroacetic acid (20 ml) and was stirred for1 hour at room temperature. The reaction mixture was concentrated underreduced pressure and the resulting residue was left under high vacuumfor 18 h. The residue was triturated in a minimal amount of diethylether and placed in an ultrasound bath for 1 hour, filtered and thendried under high vacuum to provide(2S,4R)-4-phenylpyrrolidine-2-carboxylic acid trifluoroacetic acid salt(999 mg, 99%) as solid. [M+H]⁺=192.2. ¹H NMR (300MHz,CDCl₃) δ 1.94-2.11(m, 1H), 2.61-2.75 (m, 1H), 3.09-3.22 (m, 1H), 3.42-3.59 (m, 1H),3.59-3.73 (m, 1H), 4.35-4.48 (m, 1H), 7.15-7.40 (m, 5H), 8.52-10.23 (br.s. 2H).

Step 2:(2S,4R)-4-phenyl4-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxylicacid

(2S-4R)-4-Phenylpyrrolidine-2-carboxylic acid trifluoroacetic acid salts(999 mg, 3.47 mmol) and potassium hydroxide (1.17g, 20.8 mmol) weredissolved in isopropanol (25 mL) and heated at 40° C. A solution of2-(bromomethyl)-1,3,5-trimethylbenzene (849 mg, 3.99 mmol) iniso-propanol (20 mL) was added over 60 min via a syringe. The reactionwas stirred for additional 2 h at this temperature. The reaction mixturewas treated with concentrated HCl until the pH was between 3 and 4. Theresulting solid was filtered off and the filtrate was concentrated underreduced pressure. The resultant solid was dissolved in dichloromethaneand was purified on silica gel (0-10% methanol in ethyl acetate). Upondilution of the residue with dichloromethane, the silica was filteredoff and the filtrate was concentrated under reduced pressure to provide(2S-4R)-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxylicacid (1. 1 g, 98%) as a solid. [M+H]⁺=324.2. ¹H NMR (300MHz,CDCI₃) δ2.22 (s, 3H), 2.27-2.34 (m, 1H), 2.38(s, 6H), 2.59-2.94 (m, 1H),2.96-3.30 (m, 1H), 3.36 (t, J=11.2Hz, 1H), 3.47-3.80 (m, 1H), 4,05 (m,1H), 4.20 (d, J=13.4Hz,1H), 4.35 (d, J=13.4Hz,1H), 6.83 (s, 2H),7.05-7.33(m, 5H).

Step 3:(2S,4R)—N-[(6-fluoro-2-pyridyl)sulfonyl]-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide

(2S,4R)-4-Phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxylicacid (75 mg, 0.23 mmol), 6-fluoropyridine-2-sulfonamide (192 mg, 1.09mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (497 mg, 1.31 mmol), andethyldiisopropylamine (380 μL, 2.18 mmol) were combined inN,N-dimethylformamide (1.440 mL) and heated at 60° C. for 16 h. Thereaction mixture was diluted with water (1 mL) and was extracted withethyl acetate (2×5mL). The organic layers were dried over sodiumsulfate, filtered and concentrated. The residue was subjected topreparatory-HPLC utilizing a gradient of 30-90% acetonitrile in 5 mM aqHCl to give(2S,4R)—N-[(6-fluoro-2-pyridyl)sulfonyl]-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide.¹H NMR (400 MHz, DMSO) δ 9.18 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 7.85 (d,J=9.1 Hz, 1H), 7.30 (s, 7H), 6.88 (s, 2H), 4.40 (s, 2H), 4.24 (s, 1H),3.81 (s, 1H), 3.33-3.21 (m, 2H), 2.76 (s, 1H), 2.37 (s, 6H), 2.21 (s,311), 2.00 (s, 1H).

Step 4: (2S,4R)—N-[(6-amino-2-pyridyl)sulfonyl]-4-phenyl-18(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide

(2S,4R)—N-[(6-Fluoro-2-pyridyl)sulfonyl]-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide(from step 3) was suspended in NH₄OH (2 mL of 30% w/v, 17 mmol). Themixture was heated in a microwave at 150° C. The reaction mixture wasconcentrated, redissolved in DMSO and subjected to preparatory-HPLCutilizing a gradient of 1-60% acetonitrile in 5 mM aq HCl to give(2S,4R)—N-[(6-amino-2-pyridyl)sulfonyl]-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide(Compound 236) (7.5 mg, 7% over two steps). ¹H NMR (400 MHz, MeOD) δ7.84 (s, 1H), 7.33 (s, 7H), 6.99 (d, J=8.7 Hz, 1H), 6.90 (s, 2H), 4.60(d, J=35.7 Hz, 2H), 4.41 (s, 1H), 3.98 (s, 1H), 3.76 (s, 1H), 3.67-3.55(m, 1H), 2.90 (dt, J=12.8, 6.3 Hz, 1H), 2.41 (d, J=14.1 Hz, 7H), 2.24(s, 4H). ESI-MS m/z calc. 478.2, found 479.0 (M+1)⁺; Retention time:1.41 min (3 min run).

The following compounds can be synthesized using the proceduresdescribed herein:

-   (2R,4S)—N-[(6-amino-2-pyridyl)sulfonyl]-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide    (Compound 467) and-   (2S,4S)—N-[(6-amino-2-pyridyl)sulfonyl]-4-phenyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolidine-2-carboxamide    (Compound 870)

PREPARATION 46:N-(4-Aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 265) Step 1: tert-butyl thiazol-4-ylcarbamate

A mixture of thiazole-4-carboxylic acid (8.16 g, 63.2 mmol) andtriethylaniine (9.7 mL, 70 mmol) in tert-butanol (320 mL) was treatedwith diphenyl phosphoryl azide (15 mL, 70 mmol) and heated gradually inan oil bath to 100° C. and stirred for 17 h. Once cooled, the crudereaction mixture was concentrated under reduced pressure to remove mostof the volatiles. The residue was transferred to a 1.0-L separatoryfunnel with ethyl acetate (300 mL) and the organic layer was washed withwater (2×200 mL) and brine (2×100 mL). The organic layer was then driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified silica gel chromatography, elutingfrom 0% to 50% ethyl acetate in heptanes. The resultant gummy solid wastriturated with heptanes, filtered, washed with heptanes and dried underhigh vacuum to afford tert-butyl thiazol-4-ylcarbamate (3.42 g, 27%) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.54 (s, 9 H), 7.30 (br. s, 1H), 8.33 (br. s, 1 H), 8.58 (d, J=2.3 Hz, 1 H). [M-C₄H₈+H]⁺=145.1.

Step 2: tert-butyl N-(2-sulfamoyl-1,3-thiazol-4-yl)carbamate

A solution of tert-butyl thiazol-4-ylcarbamate (1.50 g, 7.49 mmol) inmethyl tert-butyl ether (35 mL) was cooled in an ice bath and treatedslowly with iso-propylmagnesium chloride (11 mL of a 2.0 M solution inTHF, 22 mmol). A voluminous white solid appeared. After 20 minutes inthe ice bath, sulfur dioxide was gently bubbled into the reactionmixture for 5 minutes then the reaction mixture was stirred at roomtemperature for 1 h. The crude reaction mixture was concentrated underreduced pressure to remove most of the volatiles and the solid obtainedwas suspended in water (80 mL) and cooled in an ice bath. Sodium acetate(3.40 g, 41.5 mmol) and hydroxylamine-O-sulfonic acid (3.39 g. 30.0mmol) were successively added. The ice-bath was removed and the reactionwas left to stir at room temperature for 45 h. The reaction mixture wastransferred to a separatory funnel and the aqueous layer was extractedwith ethyl acetate (2×50 mL). The combined organic layers were washedwith 5% aqueous sodium bicarbonate (30 mL), brine (30 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography, elutingfrom 0% to 75% ethyl acetate in heptanes, to provide 1.2 g of a solidthat was contaminated with iso-propylsulfonamide. The solid wasdissolved in methanol (3 mL) and water (2 mL) was added dropwise withstirring. The precipitate was filtered, washed with water and driedunder high vacuum to afford tert-butylN-(2-sulfamoyl-1,3-thiazol-4-yl)carbamate (0.90 g, 43%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.46 (s, 9H), 7.56 (s, 2H), 9.12 (s,1H), 9.24 (s, 1H). [M-C₄H₈+H]⁺=224.0.

Step 3:N-[2-[[6-tert-Butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonyl]sulfamoyl]thiazol-4-yl]carbamate

K₂CO₃ (45 mg, 0.35 mmol) was added to a mixture of6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (44mg, 0.14 mmol), tert-butyl N-(2-sulfamoylthiazol-4-yl)carbamate (39 mg,0.14 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (64 mg, 0.17 mmol) and N,N-dimethylformamide(1 mL) at room temperature. The mixture was stirred at 60° C. for 3 hbefore it was cooled to room temperature. The mixture was partitionedbetween ethyl acetate and 1N HCl. The layers were separated and theaqueous layer was extracted with ethyl acetate (2×). The combinedorganics were washed with brine, dried over magnesium sulfate, filteredand concentrated. The residue was subjected to silica gel columnchromatography (0-50% ethyl acetate/hexanes), then subjected topreparatory-HPLC(10-99% acetonitrile/water with 0.05 mM HCl) to givetert-butylN-[2-[[6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonyl]sulfamoyl]thiazol-4-yl]carbamateas a white solid. ESI-MS m/z calc. 574.2, found 575.4 (M+1)⁺; Retentiontime: 2.48 min (3 min run).

Step 4:N-(4-Aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

Trifluoroacetic acid (11 μL, 0.14 mmol) was added to a mixture oftert-butylN-[2-[[6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonyl]sulfamoyl]thiazol-4-yl]carbamate(from step 3) and CH2Cl₂ (5 mL) at room temperature. The mixture wasallowed to stir for 1H before it was concentrated under reducedpressure. The residue was subjected to preparatory-HPLC (10-99%acetonitrile/water with 0.05 mM HCl) to giveN-(4-aminothiazol-2-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 265). ESI-MS m/z calc. 474.1, found 475.5 (M+1)⁺; Retentiontime: 2.11 min (3 min run). NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.07(s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 6.91 (s, 2H),6.81 (s, 2H), 2.25 (s, 3H), 1.96 (s, 6H), 1.04 (s, 9H).

The following compounds can be prepared using the procedures describedherein:

-   N-(4-aminothiazol-2-yl)sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 842) and    N-(4-aminothiazol-2-yl)sulfonyl-2-(4,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1168)

PREPARATION 47:N-[(6-Amino-2-pyridyl)sulfonyl]-6-(tert-butylamino)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 273) Step 1: methyl6-(tert-butylamino)-2-(mesityloxy)pyridine-3-carboxylate

A mixture of methyl 6-chloro-2-(mesityloxy)pyridine-3-carboxylate (170mg, 0.58 mmol) and t-butylamine (4.0 mL, 38 mmol) in 500 mLdimethylacetamide was heated in a microwave at 150° C. for 4 h. Thecrude mixture was purified by silica gel column chromatography elutingwith a gradient of 0-40% ethyl acetate/hexanes to afford methyl6-(tert-butylamino)-2-(mesityloxy)pyridine-3-carboxylate (76 mg, 38%yield) as an orange solid. LC-MS: (M+H)⁺=342.5.

Step 2: 6-(tert-butylamino)-2-(mesityloxy)pyridine-3-carboxylic acid

A mixture of methyl6-(tert-butylamino)-2-(mesityloxy)pyridine-3-carboxylate (76 mg, 0.22mmol) and sodium hydroxide (14 mg, 0.34 mmol) in methanol (1.0 mL), THF(1.0 mL), and water (0.50 mL) was heated at 60° C. for 7 h. A few dropsof concentrated HCl were added, solid formed, everything was rotaryevaporated, and dried under vacuum to give crude6-(tert-butylamino)-2-(mesityloxy)pyridine-3-carboxylic acid (98 mg) asa white solid. LC-MS: (M+H)⁺=329.3.

Step 3:6-(tert-butylamino)-2-(mesityloxy)-N-((6-nitropyridin-2-yl)sulfonyl)nicotinamide

A mixture of crude6-(tert-butylamino)-2-(mesityloxy)pyridine-3-carboxylic acid (0.22mmol), 6-nitropyridine-2-sulfonamide (58 mg, 0.29 mmol),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (0.12 g, 0.33 mmol), ethyldiisopropylamine(0.16 mL, 0.92 mmol) and N,N-dimethylformamide (1 mL) was stirred in acapped vial at 70° C. for 6 h and then at room temperature for 18 h.LC-MS at that point showed mostly the activated acid. An additional 70mg of 6-nitropyridine-2-sulfonamide and 0.080 mL ofethyldiisopropylamine were added. The mixture was stirred at 70° C. for4 h and the crude was purified twice by silica gel column chromatographyeluting with a gradient of 0-20% methanol/dichloromethane to give6-(tert-butylamino)-2-(mesityloxy)-N-((6-nitropyridin-2-yl)sulfonyl)nicotinamide(34 mg, 30% yield) as a light yellow solid. LC-MS: (M+H)⁺=514.5.

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-6-(tert-butylamino)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

A mixture of6-(tert-butylamino)-2-(mesityloxy)-N-((6-nitropyridin-2-yl)sulfonyl)nicotinamide(34 mg, 0.064 mmol) and iron metal (48 mg, 0.86 mmol) in THF (0.7 mL),EtOH (0.35 mL), conc. HCl (0.06 mL) and water (0.06 mL) was heated at60° C. for 50 min. The mixture was filtered hot and was washed withmethanol. The filtrate was rotary evaporated to give 120 mg of crudematerial which was purified by reverse phase HPLC to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-(tert-butylamino)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 273) (7.2 mg, 23%). LC-MS: (M+H)⁺=484.5.

PREPARATION 48: 6-(tert-butoxy)-2-(mesityloxy)nicotinic acid

To a solution of t-butanol (0.70 mL, 7.3 mmol, 11 eq) in 1.0 mL ofN,N-dimethylformamide was added portion-wise 60% NaH (320 mg, 8.0 mmol,12 eq). After bubbling stopped, about 10 min,6-chloro-2-(mesityloxy)pyridine-3-carboxylic acid 7 (0.20 g, 0.69 mmol,1.0 eq) was added to the reaction mixture. The mixture was heated in acapped vial at 100° C. for 22 hr. After cooling to room temperature, acouple of drops of concentrated hydrochloric acid was added and thereaction mixture was evaporated to dryness. The crude material waspurified by column chromatography using 25 g of silica gel and elutingwith a gradient of 0-30% methanol in dichlormethane over 15 minutes. Theproduct-containing fractions were combined and concentrated to afford6-tert-butoxy-2-(mesityloxy)pyridine-3-carboxylic acid (109 mg, 48%yield) as a light yellow solid. LC-MS: (M+H)+=330.1.

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(isopropylamino)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 650),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methylpyrrolidin-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1553),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-pyrrolidin-1-yl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 746),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-piperidyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 785),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-morpholino-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 966),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(methylamino)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 983),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(ethylamino)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1128),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(dimethylamino)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1306),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-ethoxy-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 637),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-methoxy-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 806),-   N-[(6-amino-2-pyridyl)sulfonyl]-8,8-dimethyl-2-(2,4,6-trimethylphenoxy)-5,7-dihydropyrano[4,3-b]pyridine-3-carboxamide    (Compound 714),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[isobutyl(methyl)amino]-5-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1416),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[(2R,5S)-2,5-dimethylpyrolidin-1-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1494),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-methyl-6-(2-methylpyrrolidin-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1516),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-2,6-bis[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1673),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-isopropoxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1573),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-5-methyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1589),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-isopropoxy-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 968), and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butoxy-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1070).

PREPARATION 49:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-cyclopentyl-pyridine-3-carboxamide(Compound 1219) Step 1:6-(tert-Butyl)-2-(cyclohex-1-en-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide

6-tert-butyl-2-chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]pyridine-3-carboxamide(75 mg, 0.20 mmol), 1-cyclohexenylboronic acid (25.41 mg, 0.2017 mmol),sodium carbonate (201.7 μL, of 2 M, 0.4034 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (7.376 mg, 0.01008 mmol) in dioxane (900.0 μL)were added to a microwave reactor vial. The vial was purged withnitrogen, capped and heated to 120° C. for 30 minutes in a microwavereactor. The reaction mixture was diluted with water and extracted withethyl acetate (2×10 mL). The organic layers were dried over sodiumsulfate, concentrated, and purified by HPLC utilizing a gradient of0-70% acetonitrile in 5 mM aq HCl to give the product (19.7 mg, 23%)ESI-MS m/z talc. 417.5, found 418.4 (M+1)⁺; Retention time: 0.64 min (1min run).

Step 2:6-(tert-butyl)-2-cyclohexyl-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide

6-(tert-Butyl)-2-(cyclohex-1-en-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide(19.7 mg, 0.047 mmol) was dissolved in methanol (10 mL) and palladium oncarbon (12.64 mg, 0.01188 mmol) was added. The mixture was stirred undera hydrogen balloon at room temperature for 16 hours. The crude materialwas filtered, concentrated, and purified by HPLC utilizing a gradient of20-80% acetonitrile in 5 mM aq HCl to give6-(tert-butyl)-2-cyclohexyl-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide.

The following compound can be synthesized using the procedures describedherein:

-   N-(4-aminophenyl)sulfonyl-6-tert-butyl-2-cyclopentyl-pyridine-3-carboxamide    (Compound 1003),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5,5-tetramethylcyclopenten-1-yl)pyridine-3-carboxamide    (Compound 1502),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(trifluoromethyl)cyclohexen-1-yl]pyridine-3-carboxamide    (Compound 1667),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,6,6-tetramethyl-3H-pyran-4-yl)pyridine-3-carboxamide    (Compound 1368),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-dimethylcyclohexen-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1493),-   and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,5,5-tetramethyl-3-furyl)pyridine-3-carboxamide    (Compound 1531).

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-cyclohexyl-pyridine-3-carboxamide(Compound 411)

6-(tert-butyl)-2-cyclohexyl-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamidewas suspended in ammonium hydroxide (1mL of 28% w/v, 8.56 mmol). Themixture was stirred in a microwave reactor for 0.5 h at 150° C. Thereaction mixture was concentrated, redissolved in DMSO and purified byHPLC utilizing a gradient of 10-65% acetonitrile in 5 mM aq HCl to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(cyclohexen-1-yl)pyridine-3-carboxamide¹H NMR (400 MHz, MeOD) 8.56 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H),7.87 (s, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 6.08 (s,1H), 2.31 (s, 2H), 2.20 (s, 2H), 1.69 (d, J=17.3 Hz, 4H), 1.53 (s, 9H).ESI-MS m/z calc. 414.17255, found 415.0 (M+1)⁺; Retention time: 1.48minutes.

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-cyclopentyl-pyridine-3-carboxamide    (Compound 1219).

PREPARATION 50:6-tert-butyl-N-[(1-methyl-2-oxo-3-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 667)

6-tert-butyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(28 mg, 0.060 mmol) was dissolved in N,N-dimethylformamide withpotassium carbonate (24.72 mg, 0.1789 mmol) and a solution ofiodomethane (8.464 mg, 3.712 μL, 0.05963 mmol) was added dropwise. Thesolution was stirred for 4 h at room temperature. The reaction mixturewas filtered and purified by LC/MS utilizing a gradient of 10-99%acetonitrile in 5 mM aq HCl to yield6-tert-butyl-N-[(1-methyl-2-oxo-3-pyridyl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 667) (2 mg, 0.004 mmol, 7%) ESI-MS m/z calc. 483.1828, found484.3 (M+1)⁺; Retention time: 2.13 minutes.

PREPARATION 51: methyl 2-(mesityloxy)-6-(prop-1-yn-1-yl)nicotinate

Prop-1-yne (25.78 μL, 0.4543 mmol) was bubbled through a solution ofN,N-dimethylformamide (2mL) and triethylamine (409.6 μL, 2.939 mmol) andthen added to a mixture of methyl6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (150. mg,0.491 mmol), dichloropalladium; triphenylphosphane (34.44 mg, 0.04907mmol), copper (I) iodide (14.02 mg, 0.07362 mmol) and triphenylphosphine (17.05 μL, 0.07359 mmol) in deoxygenated N,N-dimethylformamide(2 mL) under continous nitorgen flow. The resulting solution was purgedwith propyne and capped. The reaction was then stirred at 105° C. for 16hours. The cooled mixture was diluted with ethyl acetate and passedthrough a plug of celite, washing with ethyl acetate (10 mL). Water (7.5mL) was added to the filtrate and the layers were separated. The aqueouslayer was extracted with ethyl acetate (2×10 mL). The combined organicextracts were washed with a saturated aqueous solution of sodiumchloride (10 mL) and dried over sodium sulfate. After filtration thesolvent was removed under reduced pressure to give a dark brown residue.The residue was purified by column chromatography on silica gel eluting0-100% ethyl acetate in hexanes to yield methyl6-prop-1-ynyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (102.4mg, 0.331 mmol, 72.9%) ESI-MS m/z calc. 309.1365, found 310.2 (M+1)⁺;Retention time: 0.76 minutes.

Preparation 52:N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(trifluoromethyl)pyrazol-1-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 676)

N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(30. mg, 0.067 mmol), 5-(trifluoromethyl)-1H-pyrazole (27.41 mg, 0.2014mmol), potassium carbonate (19.49 mg, 0.1410 mmol) andtrans-diaminocyclohexane (1.534 mg, 1.613 μL, 0.01343 mmol) werecombined in N,N-dimethylformamide. At this point copper(I) iodide(0.6393 mg, 0.003357 mmol) was added and the reaction was heated at 150°C. in the microwave for 2 hours. The reaction was filtered and purifiedby LC/MS utilizing a gradient of 10-99% acetonitrile in 5 mM aq HCl toyieldN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(trifluoromethyl)pyrazol-1-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 676) (8 mg, 0.01 mmol, 20%) ¹H NMR (400 MHz, DMSO-d₆) δ 12.54(s, 1H), 8.32 (d, J=8.1 Hz, 1H), 7.85 (dd, J=2.6, 1.1 Hz, 1H), 7.69-7.62(m, 2H), 7.22 (dd, J=7.4, 0.8 Hz, 1H), 6.99 (d, J=2.6 Hz, 1H), 6.97 (s,2H), 6.72 (d, J=8.4 Hz, 1H), 6.56 (s, 2H), 2.28 (s, 3H), 2.03 (s, 6H).ESI-MS m/z calc. 546.1297, found 547.2 (M+1)⁺; Retention time: 2.1minutes.

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-pyrazol-1-yl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 564),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 633),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)pyrazol-1-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 691), and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methylpyrazol-1-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1220).

PREPARATION 53: methyl 2-(mesityloxy)-6-(1-methylcyclopropyl)nicotinate

In a microwave vial, trimethylsulfoxonium iodide (5.2 g, 23 mmol), wassuspended in anhydrous DMSO (26 mL) under nitrogen. Sodium hydride 60%in oil (1.0 g, 26 mmol) was added and the resulting solution was leftstirring 10 min. at room temperature. Methyl6-(prop-1-en-2-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (2.6g, 8.4 mmol) was added dissolved in anhydrous THF (8 mL) and leftstirring at room temperature 18 hours. The reaction mixture waspartitioned between water (100 mL) and ethyl acetate (3×100 mL),separated, then the organic phase was concentrated under reducedpressure and the resulting residue was purified on silica gel using 0 to10% ethyl acetate in heptane which provided the desired product methyl6-(1-methylcyclopropyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate(1.59 g, 58%) as a oil. ESI-MS m/z calc. 325.2, found 326.2 (M+1)⁺; ¹HNMR (300 MHz, CDCl₃) ppm: 0.60 (m, 2H), 0.84 (m, 2H), 1.36 (s, 3H), 2.01(s, 6H), 2.28 (s, 3H), 3.92 (s, 3H), 6.83 (s, 2H), 6.96 (d, J=7.9 Hz,1H), 8.16 (d, J=7.9 Hz, 1H).

PREPARATION 54: ethyl 2-(mesityloxy)-6-(1-(trifluoromethyl)cyclopropyl)nicontinate Step 1: ethyl2-(mesityloxy)-6-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazol-3-yl)nicotinate

Preparation of a solution of diazomethane in ethyl ether:N-nitriso-N-methylurea (1.87 g, 15.8 mmol) was added to a biphasicmixture of 40% aqueous KOH (6.7 mL) and diethyl ether (20 mL) cooled inan ice-bath. The mixture was stirred in the ice-bath for 20 min (turnsyellow), and then cooled in a dry-ice/acetone bath. Once the aqueouslayer was frozen, the ether layer was decanted and the yellow solutionwas kept under nitrogen until ready to use.

The above solution of diazomethane (15.8 mmol) was added dropwise to asolution of ethyl6-(3,3,3-trifluoroprop-1-en-2-yl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate(1.5 g, 3.95 mmol) in ethyl ether (20 mL) at 0° C. The yellow color ofthe diazomethane spontaneously disappeared upon addition. The reactionwas stirred at 0° C. for 30 min, and TLC showed starting material wascompletely consumed. Acetic acid (1 mL) was added to quench excess thediazomethane until it turns colorless and bubbles evolution ceased. Themixture was then diluted with ethyl acetate (50 mL), washed withsaturated aqueous sodium bicarbonate (20 mL), brine (20 mL), dried overanhydrous sodium sulfate and concentrated to give ethyl2-(mesityloxy)-6-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazol-3-yl)nicotinateas a pale yellow oil (1.7 g). ¹H NMR (300 MHz, CDCl₃) ppm, 1.40 (t,J=6.9 Hz, 3H), 1.68-1.92 (m, 2H), 1.98 (br s, 6H), 2.31 (s, 3H),3.90-4.10 (m, 1H), 4.43 (q, J=6.9 Hz, 2H), 4.64 (ddd, J=18.1, 9.5, 4.2Hz, 1H), 6.87 (s, 2H), 7.57 (d, J=7.8 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H).LCMS: [M+H]⁺=422.2.

Step 2: ethyl2-(mesityloxy)-6-(1-(trifluoromethyl)cyclopropyl)nicotinate

Ethyl2-(mesityloxy)-6-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazol-3-yl)nicotinate(1.7 g, crude, 3.9 mmol) was dissolved in m-xylene (25 mL). The solutionwas gently refluxed for 2 hours. TLC shows reaction complete. Thesolvent was removed and the residue was purified by silica gelchromatography, eluting with a mixture of ethyl acetate and heptanes(0-10%), to afford 1.6 g, crude (quantitative yield).as an unseparablemixture (1:1) of ethyl6-[1-(trifluoromethyl)cyclopropyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate,and ethyl6-[-1,1,1-trifluorobut-2-en-2-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate(undefined stereochemistry of the olefin). In order to remove thealkene, the mixture of6-[1-(trifluoromethyl)cyclopropyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylateand ethyl 6-[(2Z or2E)-1,1,1-trifluorobut-2-en-2-yl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate(1.5 g, 3.81 mmol, 1:1) was dissolved in tert-butanol (5 mL). Water (3mL) was added followed by citric acid (549 mg, 2.86 mmol) and potassiumosmium(VI) oxide dehydrate (1.4 mg). Finally, 4-methylmorpholine N-oxidemonohydrate (568 mg, 4.2 mmol) was added. The mixture was stirred atroom temperature overnight. LCMS shows 50% conversion. Potassiumosmium(VI) oxide dehydrate (1.4 mg) was added and the reaction wascontinued stirred until HPLC showed reaction was complete (approximately40 hours). The reaction was concentrated to remove most of thetert-butanol. The resulting aqueous mixture was diluted with ethylacetate (60 mL) and washed with water (10 mL), brine (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with amixture of ethyl acetate and heptanes (0-10% then 50%), to afford ethyl6-[1-(trifluoromethyl)cyclopropyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate(600 mg, 40%) as a white solid. ¹H NMR (300 MHz, CDCl₃) ppm 0.96-1.05(m, 2H), 1.15-1.23 (m, 2H), 1.39 (t, J=7.2 Hz, 3H), 2.01 (s, 6H), 2.29(s, 3H), 4.41 (q, J=7.2 Hz, 2H), 6.85 (s, 2H), 7.25 (d, J=8.2 Hz, 1H),8.21 (d, J=8.2 Hz, 1H). LCMS: [M+H]⁺=394.0.

PREPARATION 55: ethyl 2-(mesityloxy)-6-(perfluoroethyl)nicotinate

In a sealed tube, 3-(ethoxycarbonyl)-2-(mesityloxy)pyridine 1-oxide(1.85 g, 6.14 mmol) was dissolved in anhydrous tetrahydrofuran (18.5 mL)with flame dried (under high vacuum) cesium fluoride (93 mg, 0.05 mmol)then trimethyl(pentafluoroethyl)silane (3.53 g, 18.4 mmol) was added at0° C. and the reaction mixture was stirred at room temperature undernitrogen for 5 days. Distilled water (10 mL) and ethyl acetate (50 mL)were added to the crude material. The organic phase was separated, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified on silica gel using 0-10%ethyl acetate in heptane to provide ethyl6-(pentafluoroethyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate(480 mg, 25%) as an oil. [M+H]⁺=404.1 ¹H NMR (300 MHz, CDCl₃) ppm: 1.41(t, J=7.1 Hz, 3H), 2.03 (s, 6H), 2.29 (s, 3H), 4.45 (q, J=7.1 Hz, 2H),6.87 (s, 2H), 7.39 (d, J=7.7 Hz, 1H), 8.36 (d, J=7.8 Hz, 1H).

PREPARATION 56: tert-butyl (4-sulfamoylthiazol-2-yl)carbamate Step 1:lithium (tert-butoxycarbonyl)(4-sulfinatothiazol-2-yl)amide

Methyllithium (0.70 mL, 1.6 M in diethyl ether, 1.1 mmol) was added to asolution of tert-butyl N-(4-bromo-1,3-thiazol-2-yl)carbamate (279 mg,1.00 mmol) in anhydrous tetrahydrofuran (2 mL) and anhydrous diethylether (2 mL) at −78° C. After 5 min, tert-butyl lithium (1.2 mL, 1.7 Min pentane, 2 mmol) was added at −78° C. A light yellow suspension wasformed. After 20 min, sulfur dioxide (gas) was bubbled into the reactionat −78° C. for 5 min. A yellow clear solution was obtained. The reactionwas allowed to slowly warm up to room temperature and stirred overnight.The reaction mixture was concentrated to dryness and the residue wastriturated with diethyl ether (10 mL) to afford a light yellow solid(390 mg), which is a mixture of lithium(tert-butoxycarbonyl)(4-sulfinatothiazol-2-yl)amide and lithium bromide.[M+Na]⁺=287.0.

Step 2: tert-butyl (4-sulfamoylthiazol-2-yl)carbamate

Hydroxylamine-O-sulfonic acid (147 mg, 1.2 mmol) was added to a solutionof lithium 2-{[(tert-butoxy)carbonyl]amino)-1,3-thiazole-4-sulfinate(330 mg, containing lithium bromide, 0.91 mmol) and sodium acetate (148mg, 1.8 mmol) in water (4 mL) at 0° C. The reaction was stirred at roomtemperature for 2 hours. Copious amounts of solids precipitated out.HPLC showed complete conversion. The mixture was stirred at 0° C. for 5min. The solid was filtered off, washed with cold water (1 mL) and driedunder high vacuum to afford tert-butylN-(4-carbamoyl-1,3-thiazol-2-yl)carbamate (130 mg, 51%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.49 (s, 9H), 7.43 (s, 2H), 7.67 (s,1H), 11.84 (br. s, 1H). [M+Na]⁺=302.0.

PREPARATION 57: tert-butyl ((6-sulfamoylpyridin-2-yl)methyl)carbamate

A solution of 6-cyanopyridine-2-sulfonamide (1.00 g, 5.46 mmol) inmethanol (25 mL) and ammonia (5 mL of a 7.0 N solution in methanol, 35mmol) was treated with a spatula of Raney-Nickel (2800, slurry inwater). The flask was purged three times with hydrogen then left to stirat room temperature under one atmosphere of hydrogen for 18 hours. Thecrude reaction mixture was filtered over a pad of celite, washed withmethanol, and concentrated under reduced pressure. The residue was takenup in dichloromethane (25 mL) and treated successively withtriethylamine (1.52 mL, 10.9 mmol) and di-tert-butyl dicarbonate (1.55g, 7.10 mmol). After about 1 hour, tetrahydrofuran (10 mL) was added inan attempt to help solubilize the reaction mixture. After another hour,the reaction was concentrated under reduced pressure, transferred to a250-mL separatory funnel with water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified on 40 g of silica gelutilizing a gradient from 50% to 100% ethyl acetate in heptanes toafford tert-butyl ((6-sulfamoylpyridin-2-yl)methyl)carbamate (217 mg,14%) as a white solid. ¹H NMR (300 MHz, Acetone-d₆) ppm 1.43 (s, 9 I-I),4,43 (d, J=6.0 Hz, 2H), 6.48-6.77 (m, 3H), 7.58 (d, J=7.8 Hz, 1H), 7.83(d, J=7.8 Hz, 1H), 7.97-8.10 (m, 1H). [M+Na]⁺=310.1.

PREPARATION 58:N-(2-aminothiazol-5-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 1148)

In a 4mL vial a solution ofN-(2-acetamidothiazol-5-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(14.6 mg, 0.0269 mmol) and aqueous hydrochloric acid (268.5 μL of 4 M,1.074 mmol) in dioxane (277.4 μL) was stirred at 90° C. for 1 hour. Thereaction mixture was cooled and purified directly by reverse-phasepreparative chromatography utilizing a Cl8 column and a gradient of30-99 acetonitrile in water containing 5 mM hydrochloric acid to affordN-(2-aminothiazol-5-yl)sulfonyl-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 1148) (5.9 mg, 0.012 mmol, 45%) as a white solid. ¹H NMR (400MHz, DMSO) δ 12.10 (s, 1H), 8.02 (s, 2H), 7.95 (d, J=7.8 Hz, 1H), 7.67(s, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.90 (s, 2H), 2.25 (s, 3H), 1.97 (s,7H), 1.04 (s, 10H). ESI-MS m/z calc. 474.1, found 475.2 (M+1)⁺;Retention time: 2.11 minutes.

PREPARATION 59:6-(tert-butyl)-2-(mesityloxy)-4-methoxy-N-((3-nitrophenyl)sulfonyl)nicotinamide

In a 10 mL microwave vessel was added6-tert-butyl-N-(3-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(85 mg, 0.17 mmol) dissolved in anhydrous methanol (684.1 mg, 864.9 μL,21.35 mmol) and xylene (850.0 μL) and to it was added diacetoxypalladium(3.835 mg, 0.01708 mmol), (diacetoxyiodo)benzene (165.0 mg, 0.5124mmol), and 4 Angstrom molecular sieves. The mixture was heated in an oilbath to 100° C. for 18 hours. A second aliquot of diacetoxypalladium(3.835 mg, 0.01708 mmol) was added and the reaction mixture heated in anoil bath to 100° C. for an additional 48 hours. The mixture was allowedto cool and the mixture was filtered and the resulting solution waspurified by reverse-phase preparative chromatography utilizing a C18column and a gradient of 30-99 acetonitrile in water containing 5 mMhydrochloric acid to afford6-tert-butyl-4-methoxy-N-(3-nitrophenyl)sulfonyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(20.7 mg, 0.0388 mmol, 23%). ¹H NMR (400 MHz, DMSO) 12.89 (s, 1H), 8.61(t, J=2.0 Hz, 1H), 8.49 (d, J=8.2 Hz, 1H), 8.36 (d, J=8.1 Hz, 1H), 7.92(t, J=8.1 Hz, 1H), 6.82 (s, 2H), 6.72 (s, 1H), 3.84 (s, 3H), 2.22 (s,3H), 1.86 (s, 6H), 1.03 (s, 10H). ESI-MS m/z calc. 527.1726, found 528.2(M+1)⁺; Retention time: 2.2 minutes.

PREPARATION 60:2-chloro-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrileStep 1: 5-(hydroxymethylene)-3,3-dimethyltetrahydro-4H-pyran-4-one

To a solution of 3,3-dimethyltetrahydropyran-4-one (1.8 g, 14 mmol) inether (50 mL) was added ethyl formate (1.040 g, 1.134 mL, 14.04 mmol).The mixture was cooled to 0° C. Sodium ethoxide (1.051 g, 15.44 mmol)was added at 0° C. The mixture was allowed to warm to room temperature,stirred overngiht and then evaporated to dryness. The crude material wasused directly in next step without further purification.

Step 2:2-hydroxy-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile

To a suspension of5-(hydroxymethylene)-3,3-dimethyl-tetrahydropyran-4-one (2.2 g, 14 mmol)in pyridine (100 mL) was added 2-cyanoacetamide (1.177 g, 14.00 mmol).The mixture was heated at reflux overnight. The reaction mixture wasevaporated to dryness and the residue was partitioned between ethylacetate and water. The aqueous layer was extracted thee times with ethylacetate, and then three times with a 2:1 mixture of dichloromethane andisopropanol. The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and evaporated to dryness. The residuewas washed with methanol to yield the product (205 mg, 1.00 mmol, 7.1%).¹H NMR (400 MHz, Chloroform-d) δ 7.55 (s, 1H), 4.54 (s, 2H), 3.61 (s,2H), 3.49 (s, 1H), 1.42 (s, 6H).

Step 3:2-chloro-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile

A mixture of2-hydroxy-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile(240. mg, 1.17 mmol) in phosphorous oxychloride (2.5 mL, 26.82 mmol) washeated to 105° C. for 6 hours. The reaction mixture was evaporated todryness. The residue was added dropwise to water, and then extractedthree times with ethyl acetate. The combined organic layers were washedwith brine, dried over magnesium sulfate, filtered, and concentrated todryness. The crude material was purified by silica gel columnchromatography (0-10% ethyl acetate in hexanes) to provide2-chloro-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile(240. mg, 1.08 mmol, 92.3%) as a yellow solid. ¹H NMR (400 MHz,Chloroform-d) δ 7.57 (s, 1H), 4.78 (d, J=0.9 Hz, 2H), 3.71 (s, 2H), 1.33(s, 6H).

PREPARATION 61:6-(tert-butyl)-2-(mesityloxy)-N—(N-methyl-3-nitrophenylsulfonimidoyl)nicotinamide

To a solution ofrac-6-tert-butyl-N-(3-nitrobenzenesulfinyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(253 mg, 0.525 mmol) in acetonitrile (4.1 mL) was addedN-chlorosuccinimide (217 mg, 1.63 mmol) at 0° C. The mixture was thenstirred at room temperature until no more starting material was left(about 1 hour). Methylamine (0.79 mL of a 2.0 M solution in THF, 1.6mmol) was added to the reaction at 0° C. and the mixture was stirred for1 hour at room temperature and then quenched by the addition of water (3mL). The mixture was extracted with ethyl acetate (2×10 mL), the organiclayers were combined, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified on 25 g ofsilica gel utilizing a gradient of 0% to 45% ethyl acetate in heptanesto afford6-(tert-butyl)-2-(mesityloxy)-N—(N-methyl-3-nitrophenylsulfonimidoyl)nicotinamide(170 mg, 63% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) ppm 1.06(s, 9H), 2.02 (s, 6H), 2.28 (s, 3H), 2.78 (s, 3H), 6.83 (s, 2H), 6.91(d, J=7.8 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.38(d, J=8.3 Hz, 1H), 8.45 (d, J=7.7 Hz, 1H), 8.83-8.87 (m, 1H).[M+H⁺=511.1.

PREPARATION 62:N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methoxy-2-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 470) Step 1:N-((6-aminopyridin-2-yl)sulfonyl)-2,6-dichloronicotinamide

2,6-dichloro-pyridine-3-carboxylic acid (20.2 g, 105 mmol) was dissolvedin N,N-dimethylformamide (200 mL) and stirred under nitrogen and CDI(25.5 g, 158 mmol) was added in one portion. The reaction was warmed to65° C. and heated for 1 h. In a separate vessel,6-aminopyridine-2-sulfonamide (18.2 g, 105 mmol) was dissolved inN,N-dimethylformamide (100 mL) under nitrogen and NaH (4.40 g, 60%, 110mmol) was added in portions to mitigate gas evolution and the reactionwas stirred for 1 h. The two reactions were combined in one portion at65° C. The reaction was stirred for 30 min and evaporated to remove mostof N,N-dimethylformamide. The residue was poured over ice and madeacidic (pH=˜3) by the addition of 6M HCl. Solid was collected byfiltration and washed with water (100 mL) and methanol (30 mL) andcombined to the following crude material after dried. The filtrate andwashing were combined and extracted with ethyl acetate (3×500 mL). Theorganics were washed once with brine (500 mL), dried over sodium sulfateand evaporated. The crude material was suspended in a mixture solvent ofdichloromethane/ethyl acetate/methanol (30/30/30 mL), the suspensionsonicated for 30 min, and filtered. The solid washed with ether (2×150mL) and dried to give 19.8 g white solid (54%). The filtrate was furtherconcentrated to afford 6.0 g (16%) of product. LCMS: 347 [M+H]+; NMR(DMSO-d₆, 250 MHz): 8.11 (d, J=7.5 Hz, 1H), 7.80-7.55 (m, 2H), 7.19 (d,J=7.2 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 6.71 (s, 2H) ppm

Step 2:N-((6-aminopyridin-2-yl)sulfonyl)-6-chloro-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide

N-[(6-amino-2-pyridyl)sulfonyl]-2,6-dichloro-pyridine-3-carboxamide(1.02 g, 2.94 mmol), 2,2,4-trimethylpyrrolidine (Hydrochloric Acid (1))(1.319 g, 8.814 mmol), and potassium carbonate (2.030 g, 14.69 mmol)were combined in dimethylsulfoxide (8.160 mL) and heated at 100° C. for16 h. The reaction was diluted with water and the pH was adjusted to 7.The aqueous mixture was extracted with ethyl acetate (3×100 mL). Theorganics were combined, washed with brine, dried over sodium sulfate andevaporated. The crude material was purified by silica gel chromatographyeluting with 0-100% ethyl acetate in hexanes to yieldN-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(700. mg, 1.65 mmol, 56.2%) ESI-MS m/z calc. 423.1132, found 424.2(M+1)⁺; Retention time: 0.63 minutes.

Step 3:

N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(42 mg, 0.10 mmol), (5-methoxy-2-methyl-phenyl)boronic acid (25 mg, 0.15mmol), tetrakis(triphenylphosphine)palladium (O) (11 mg, 0.010 mmol),and 2M aqueous potassium carbonate (0.2 mL, 4 mmol) were combined inN,N-dimethylformamide (1 mL) and irradiated in the microwave reactor for20 min at 120° C. The reaction was filtered and purified by LC/MSutilizing a gradient of 10-99% acetonitrile in 5 mM aq HCl to yieldN-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methoxy-2-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 470) as a hydrochloric acid salt (12 mg, 0.022 mmol, 22%).ESI-MS m/z calc. 509.21, found 510.5 (M+1)⁺; Retention time: 1.42minutes.

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl[-6-(o-tolyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 761),-   N-(benzenesulfonyl)-6-(3-fluoro-5-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1538),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-cyclopropyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1627),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1636)-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 630),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 890),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 852),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 946),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,4-dimethylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 614),-   tert-butyl    545-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate    (Compound 1371),-   N-[(6-amino-2-pyridyl)sulfonyl]-3-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-5-(6-isopropoxy-3-pyridyl)pyrazine-2-carboxamide    (Compound 1651),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-isobutoxy-phenyl)-3-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrazine-2-carboxamide    (Compound 1526),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-norbornan-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1378),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-isopropenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1423),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6,6-dimethyl-2,3-dihydropyran-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1369),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-dihydro-2H-pyran-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1438),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-dihydrofuran-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1455),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2-dimethylpropyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1489),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1500),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1503),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2-dimethylprop-1-enyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1510),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-dihydro-2H-pyran-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1524),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydrofuran-3-yl-2-8    (4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound    1534),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydropyran-3-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1632),-   6-(1-acetyl-4-piperidyl)-N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1634) (Compound 946),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexen-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1664),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-cyclopropylethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1677),-   N-[(6-amino-2-pyridyl)sulfonyl]-644-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1672),-   N-[(6-amino-2-pyridyl)sulfonyl[-6-(2-hydroxy-5,5-dimethyl-cyclohexyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1439),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,3-dimethyl-6-oxo-cyclohexen-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1462),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-isopropyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1505),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-ethyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1507),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,6-dihydro-2H-pyran-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1594),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydropyran-4-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1595),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-isobutyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1599),-   tert-butyl    445-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate    (Compound 1624),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methylprop-1-enyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1683),-   tert-butyl    4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]-2,3-dihydropyrrole-1-carboxylate    (Compound 1684),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluoro-2-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 822),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-phenyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1334),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 712),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-fluoro-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1099),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(p-tolyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 456),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 695),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1194),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-propoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 644),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1021),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 440),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 693),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 504),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1020),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1100),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 847),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1109),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1094),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 1266),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-propoxy-phenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 692),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(4-methyl-1-piperidyl)pyridine-3-carboxamide    (Compound 777),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrroliclin-1-yl]-6-phenyl-pyridine-3-carboxamide    (Compound 805),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-fluorophenyl)pyridine-3-carboxamide    (Compound 1029),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-methoxyphenyl)pyridine-3-carboxamide    (Compound 1215),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-ethoxy-5-fluoro-phenyl)pyridine-3-carboxamide    (Compound 551),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 459),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1197),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isobutoxyphenyl)pyridine-3-carboxamide    (Compound 563),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isopropylphenyl)pyridine-3-carboxamide    (Compound 1343),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 788),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 773),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(2-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 807),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-isobutoxyphenyl)pyridine-3-carboxamide    (Compound 957),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dirnethylpyrrolidin-1-yl]-6-(6-methoxy-2-pyridyl)pyridine-3-carboxamide    (Compound 1141),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(p-tolyl)pyridine-3-carboxamide    (Compound 1078),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(4-fluoro-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2472),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2587),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1967),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2199),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(m-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2339),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1819),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2-fluoro-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2016),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2666),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2240),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2229),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(4-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2327),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1947),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2-ethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2050),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2,3-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2110),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-ethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2570),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3,5-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1716),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(4-ethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2525),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2,5-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2489),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1897),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2156),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(4-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2120),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-[2-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2070),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-phenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1725),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-[3-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2029),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2045),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-[4-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1763),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2414),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-[3-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2220),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-[4-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1900),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3,5-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1839),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3,4-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2605),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2,3-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2225),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(2,5-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1736),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(5-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2490),-   2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-ethoxy-5-fluoro-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 382),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-isobutoxyphenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 710),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(2-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 681),-   6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 832),-   6-(4-chloro-3-isobutoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1234),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-methoxy-2-pyridyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1236),-   6-(4-chloro-3-isopropoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 701),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isopropoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1285),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isobutoxyphenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 1335),-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isopropylphenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide    (Compound 414),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1269),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 995),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxyphenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 455),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-methoxyphenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 833),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluorophenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 763),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-5-methyl-pyridine-3-carboxamide    (Compound 483),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)-5-methyl-pyridine-3-carboxamide    (Compound 486),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methoxy-2-methyl-phenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1287),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-methoxy-pyridine-3-carboxamide    (Compound 1254),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 643),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 896),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropyl-4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1262),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isopropylpyrazol-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1067),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isobutylpyrazol-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 631),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropylpyrazol-3-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1242),-   N-[(6-amino-2-pyridyl)sulfonyl]-642-[isobutyl(methyl)amino]-4-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 898),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxypyrazin-2-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1252),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-isopropoxypyrazin-2-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 965)-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropoxypyrimidin-5-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 844),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-2-methyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 616),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1424),-   N-(benzenesulfonyl)-6-[3-fluoro-5-(3-hydroxy-2-methyl-propoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrroliclin-1-yl]pyridine-3-carboxamide    (Compound 1515),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-(3-hydroxy-2-methyl-propoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1567),-   N-(benzenesulfonyl)-6-[3-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1581),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(5-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 400),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[5-(cyclopentoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 495),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 526),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dirnethylpyrrolidin-1-yl]-6-(5-isobutoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1224)-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[(E)-2-cyclopropylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1379),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2291),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1822),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,5-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2105),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-ethoxy-3-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2403),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1871),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2205),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrroliclin-1-yl]pyridine-3-carboxamide    (Compound 2623),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(5-ethoxy-2-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2149),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-2-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1847),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxy-4-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1808),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-5-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2018),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-4-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2665),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-chlorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2183),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methyl-1-naphthyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2126),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2539),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(trifluoromethoxy)phenyl1-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2245),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2223),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2040),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4,5-difluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2334),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2593),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-difluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2006),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(o-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1766),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2048),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-difluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2302),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-difluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2457),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-difluoro-5-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1998),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxy-2,3-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2450),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2447),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2164),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1H-indol-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2054),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2241),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1-methylindol-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2401),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-cyanophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2437),-   tert-butyl    2-[5-[(2-amino-3-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]indole-1-carboxylate    (Compound 2657),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1790),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-ethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1945),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1873),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-cyanophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1824),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2435),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-cyanophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2096),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1731),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-2-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2446),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1714),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1-isopropylpyrazol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2290),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxy-2,6-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2607),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1-isobutylpyrazol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2231),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2244),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1980),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxy-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2646),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(dimethylamino)-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2319),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methoxy-2-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1866),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(hydroxymethyl)-5-methoxy-phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2065),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2564),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-isoquinolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2418),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(5-fluoro-6-methoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2628),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1854),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methoxy-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2268),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,6-dimethoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2091),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2272),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1713),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2367),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-dimethylisoxazol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2215),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-hydroxy-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1999),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(difluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2644),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(m-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1829),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(p-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2132),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluoro-2-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2653),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(5-fluoro-2-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2046),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2349),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,5-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1951),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-dihydrobenzofuran-7-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2163),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1747),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2592),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2426),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2380),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(hydroxymethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1738),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-methoxy-4-methyl-phenyl)-2[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2379),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(5-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2660),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-3-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2158),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2413),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1851),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-isobutyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2150),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-6-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2033),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-3-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2562),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2664),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(5-fluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2189),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluoro-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2052),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-5-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2474),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2482),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1869),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1818),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2355),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(hydroxymethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2590),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluoro-3-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2124),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2345),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-naphthyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2280),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1-naphthyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1857),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-phenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1958),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-chlorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2066),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2127),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4,5-trifluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2035),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2613),-   N4(2-amino-3-pyridyl)sulfonyl]-6-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2522),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-isopropylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2172),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2667),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1964),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2515),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2017),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1903),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1944),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-isobutoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2448),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isopropylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1991),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,6-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1994),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2368),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2436),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2257),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,5-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2195),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-hydroxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1820),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(hydroxymethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1706),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-hydroxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1712),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1705),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2505),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1962),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1825),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxy-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2494),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(hydroxymethyl)-4-methoxy-phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1707),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4-dimethoxypyrimidin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2008),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluoro-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrradin-1-yl]pyridine-3-carboxamide    (Compound 1930),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1922),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxy-2,5-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2227),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1910),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2616),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2658),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2638),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,2-difluoro-1,3-benzodioxol-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2104),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-hydroxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2232),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2372),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2236),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2203),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2034),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2566),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-2-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2386),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2555),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxy-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2043),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2559),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1969),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1785),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-difluoro-4-isopropoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2608),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-4,5-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1931),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2392),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1771),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methyl-2-propoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2085),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2296),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2287),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isobutylpyrazol-3-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2114),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2366),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(difluoromethoxy)-3-methyl-phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2543),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2394),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxy-2-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 536), and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methoxy-2,5-dimethyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1259).

PREPARATION 63:N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(cyclopropylmethoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 789)

N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-fluoro-3-pyridyl)pyridine-3-carboxamide(50. mg, 0.11 mmol) and cyclopropylmethanol (77 mg, 1.1 mmol) werecombined in DMSO (1 mL), cooled down to 0° C. and NaH (12.75 mg, 0.5315mmol) was added to the reaction mixture. The mixture was heated to 90°C. for 3 h. The reaction mixture was filtered and then purified using areverse phase HPLC-MS method using a Luna C18 column (50×21.2 mm, 5 μmparticle size) sold by Phenomenex (pn: 00B-4252-P0-AX), and a dualgradient run from 1-99% mobile phase B over 15.0 minutes. Mobile phaseA=H₂O (containing 5 mM HCl). Mobile phase B=CH₃CN. Flow rate=35 mL/min,injection volume=950 μL, and column temperature=25° C. The UV absorptionat 254 nm is used to collect fractions. The desired fractions werecollected, neutralized with 20 mL of NaHCO₃, extracted with ethylacetate, washed with brine, dried over sodium sulfate, filtered, andconcentrated to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(cyclopropylmethoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 789) (24 mg, 0.046 mmol, 42%). 1H NMR (400 MHz, DMSO-d₆) δ8.78 (d, J=2.4 Hz, 1H), 8.28 (dd, J=8.7, 2.5 Hz, 1H), 7.60-7.42 (m, 2H),7.01 (bs, 2H), 6.87 (d, J=8.7 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 6.23 (bs,2H), 4.23 (s, 2H), 4.13 (d, J=7.1 Hz, 2H), 1.86 (bs, 2H), 1.56 (bs, 2H),1.25 (dddd, J=11.9, 7.3, 5.4, 2.6 Hz, 1H), 1.04 (d, J=6.1 Hz, 6H),0.59-0.49 (m, 2H), 0.36-0.26 (m, 2H). ES:[-MS m/z calc. 522.2049, found523.3 (M+1)⁺; Retention time: 1.96 minutes

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1270),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1656),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1512),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1637),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(difluoromethoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1679),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isobutoxy-2-methyl-3-pyridyl)pyridine-3-carboxamide    (Compound 1537),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethyl-methyl-amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2684),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-ethoxyethyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2685),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-ethoxyethylamino)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2686),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-2-methyl-3-pyridyl)pyridine-3-carboxamide    (Compound 1623),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-4-methyl-3-pyridyl)pyridine-3-carboxamide    (Compound 1514),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-(isobutylamino)-3-pyridyl]pyridine-3-carboxamide    (Compound 1398),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[[(1S)-1,3-dimethylbutyl]amino]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1463),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S    ,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-[isobutyl(methyl)amino]-3-pyridyl]pyridine-3-carboxamide    (Compound 1506),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-[6-(1-ethylpropylamino)-3-pyridyl]pyridine-3-carboxamide    (Compound 1397),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[[(1S)-1,2-dimethylpropyl]amino]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1399),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isopropyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2687),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isopropylamino)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2688),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[ethyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2689),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[[(1R)-1,2-dimethylpropyl]amino]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1442),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[[(1R)-1,3-dimethylbutyl]amino]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1527),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isobutoxy-2-pyridyl)pyridine-3-carboxamide    (Compound 389),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 397),-   methyl    2-[[5-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-2-pyridyl]-2-pyridyl]oxy]propanoate    (Compound 723),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxypyrazin-2-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1523),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isobutyl(methyl)amino]-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 412),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isobutoxy-2-pyridyl)pyridine-3-carboxamide    (Compound 432),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isopropylamino)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 437),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 471),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isobutoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 544),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isobutylamino)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 569),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(1-ethylpropoxy)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 580),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 708),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(1,2-dimethylpropoxy)-2-pyridyl]-2-(2,2-dimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 717),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)pyrazin-2-yl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 779),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 796),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-2-methyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 814),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isobutyl(methyl)amino]-2-methyl-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 827),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(1,3-dimethylbutoxy)-2-pyridyl]-2-(2,2-dimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 846),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopentyloxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 848),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-4-methyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 851),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-4-methyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 905),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isopropylamino)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 951),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxypyrazin-2-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 988),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(6-isobutoxy-2-pyridyl)pyridine-3-carboxamide    (Compound 1011),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isobutylamino)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1059),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1062),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(1-ethylpropoxy)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1076),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopentyloxy-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1135),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-4-methyl-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1160),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1181),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-2-pyridyl]-2-(2,2-dimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1328),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1345),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(1,3-dimethylbutoxy)-4-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 384),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(isobutylamino)-4-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 523),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-propoxy-4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 491),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isobutoxy-4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1192),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropoxy-4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 402),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isobutoxy-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1618),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-3-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1645),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-3-methyl-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1659),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1663),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-5-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1610),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-5-methyl-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1363),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-3-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1383),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isobutylamino)-3-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1417),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1504),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(cyclobutoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 428),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-(2-hydroxy-1-methyl-ethoxy)-3-pyridyl]pyridine-3-carboxamide    (Compound 998),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[(1R)-2-benzyloxy-1-methyl-ethoxy]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 576),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1727),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1915),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1741),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isobutyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2279),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[5-methyl-6-[(1R)-1-methylpropoxy]-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2576),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2170),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethoxyl-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1715),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[5-methyl-6-[(1S)-1-methylpropoxy]-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1728),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-[2-(2-isopropoxyethoxy)ethoxy]ethoxy]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1787),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-(3-but-3-ynyldiazirin-3-yl)ethoxy]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-ethoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2404),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-isopropoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1973),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-methoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2582),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(2-ethoxyethoxy)-6-methyl-4-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1948),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(2-isopropoxyethoxy)-6-methyl-4-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2079),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(diethylamino)-6-methyl-4-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1739),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isobutoxy-6-methyl-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2010),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[2-[2-(2-ethoxyethoxy)ethoxy]-6-methyl-4-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1812),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxy-6-methyl-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2364),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropoxy-6-methyl-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2306),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methoxy-6-methyl-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1748),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1702),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(2-ethoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2497),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-ethoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2651),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethoxy]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1783),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(2-isopropoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1695),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-[(1-methylcyclopropypmethoxy]-3-pyridyl]pyridine-3-carboxamide    (Compound 454), and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(cyclopropoxy)-3-pyridyl]-2-[(28,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1125).

PREPARATION 64:1-Methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylic acidStep 1: 2-Benzyl 1-(tert-butyl) 1-methylisoindoline-1,2-dicarboxylate

A solution of tert-butyl2-[benzyloxycarbonyl-[(2-bromophenyl)methyl]amino]propanoate (2.69 g,6.00 mmol) in dioxane (30 mL) was purged with nitrogen for 2 minutes.2-(2-Diphenylphosphanylphenyl)-N,N-dimethyl-aniline (228.9 mg, 0.6000mmol) was added under nitrogen followed by the addition oftris(dibenzylideneacetone)dipalladium(0) (274.7 mg, 0.3000 mmol).Lithium tert-butoxide (960.7 mg, 12.00 mmol) was added to the reactionmixture. The mixture was heated to 90° C. for 16 hours, diluted withethyl acetate and filtered. The residue was purified by silica gelcolumn chromatography (0-10% ethyl acetate in hexanes) to provide2-benzyl 1-(tert-butyl) 1-methylisoindoline-1,2-dicarboxylate (1.4 g,3.8 mmol, 63%). ESI-MS m/z calc. 367.17834, found 368.4 (M+1)⁺;Retention time: 2.75 minutes.

Step 2: tert-butyl 1-methylisoindoline-1-carboxylate

A solution of 2-benzyl 1-(tert-butyl)1-methylisoindoline-1,2-dicarboxylate (718 mg, 1.95 mmol) in methanol(50 mL) was purged with nitrogen for 2 minutes. Palladium on carbon (10%w/w, 104.0 mg, 0.09770 mmol) was added and the mixture was placed underan atmosphere of hydrogen for 16 hours. The catalyst was removed viafiltration through celite and the filtrate was concentrated to drynessto provide tert-butyl 1-methylisoindoline-1-carboxylate (400. mg, 1.71mmol, 87.7%). The crude material was used directly in next step withoutfurther purification.

Step 3:1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylic acid

To a solution of tert-butyl 1-methylisoindoline-1-carboxylate (1.5 g,6.4 mmol) in acetonitrile (75.00 mL) was added2-(chloromethyl)-1,3,5-trimethyl-benzene (1.084 g, 6.429 mmol) andcesium carbonate (4.190 g, 12.86 mmol). The mixture was heated at 90° C.overnight, and then partitioned between ethyl acetate and water. Theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over magnesium sulfate, filtered,and concentrated to dryness. The crude material was purified by silicacolumn chromatography utilizing a gradient of 0-5% ethyl acetate inhexanes to provide tert-butyl1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylate.This material was then dissolved in dioxane (3.2 mL) and hydrochloricacid in dioxane (5 mL of 4 M, 20.00 mmol) was added to the mixture. Themixture was stirred for 16 hours at room temperature. The mixture wasthen stirred at 70° C. for 1 hour. The reaction mixture was cooled toroom temperature, the precipitate was filtered and washed with dioxaneto give an off-white solid.1-methyl-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxylic acid(0.98 g, 3.2 mmol, 49%) ESI-MS m/z talc. 309.17288, found 310.5 (M+1)⁺;Retention time: 1.18 minutes (3 min run).

PREPARATION 65: Ethyl 5-methyl-1-(p-tolyl)-1H-indole-2-carboxylate

A mixture of ethyl 5-methyl-1H-indole-2-carboxylate (2.032 g, 10.00mmol), 1-iodo-4-methyl-benzene (2.180 g, 10.00 mmol), iodocopper (95.22mg, 0.5000 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (284.5 mg, 315.4μL, 2.000 mmol), and potassium phosphate (4.458 g, 21.00 mmol) intoluene (50.00 mL) was heated to reflux for 22 hours. The cooledreaction was filtered and evaporated. The green residue was purified bysilica gel chromatography with 0-15% ethyl acetate in hexanes to giveethyl 5-methyl-1-(p-tolyl)-1H-indole-2-carboxylate (1.43 g, 4.875 mmol,48.74%) as a colorless oil. ESI-MS m/z talc. 293.14, found 294.2 (M+1)⁺;Retention time: 0.83 minutes (1 minute run).

PREPARATION 66:N-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 390)

N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(147.4 mg, 0.2887 mmol) in acetic acid (1.5 mL) was treated with bromine(69.20 mg, 22.31 μL, 0.4330 mmol) and stirred at room temperature for 1hour. The resulting yellow suspension was diluted with water (20 mL),quenched to pH 2-3 by addition of saturated aqueous sodium bicarbonateand extracted with dichloromethane. The crude material was purified bychromatography over silica gel (12g) with a linear gradient of 0 to 5%methanol in dichloromethane to giveN-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(Compound 390) (90. mg, 0.14 mmol, 50.%) as a yellow foam. ¹H NMR (400MHz, DMSO-d₆) δ 12.80 (s, 1H), 8.52 (dd, J=2.5, 0.7 Hz, 1H), 8.02 (dd,J=8.7, 2.5 Hz, 1H), 7.85 (s, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.2Hz, 1H), 6.83 (dd, J=8.6, 0.7 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.51 (s,2H), 5.32 (p, J=6.2 Hz, 1H), 3,95 (s, 2H), 1.97-1.82 (m, 2H), 1.64 (dd,J=8.9, 5.3 Hz, 2H), 1.33 (d, J=6.2 Hz, 6H), 1.04 (d, J=6.1 Hz, 6H).ESI-MS m/z calc. 588.1154, found 589.0 (M+1)⁺; Retention time: 2.25minutes.

PREPARATION 67:3-(tert-butyl)-4-methoxy-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxylicacid Step 1:3-(tert-butyl)-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide

In a 20 mL sealed flask containing5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylic acid1 (500. mg, 1.66 mmol) was added N-methylpyrrolidinone (5.000 mL) anddiisopropylamine (537.7 mg, 724.7 μL, 4.160 mmol) followed by apropylphosphonic anhydride solution (2.118 mL of 50% w/v, 3.328 mmol)and 2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline (426.5 mg, 1.830mmol) and the resulting mixture was stirred at 80° C. for 16 hours. Thematerial was diluted with ethyl acetate (10 mL), washed with water andthe organic layer was extracted. The organic layer was washed twice witha saturated aqueous solution of sodium bicarbonate, followed by brine.The material was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The resulting crude material was adsorbed tocelite and purified by silica gel column chromatography ((40 g) using agradient of 0 to 50% ethyl acetate) to afford5-tert-butyl-N-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(748 mg, 1.44 mmol, 86.4%). ESI-MS m/z calc. 515.1808, found 516.2(M+1)⁺; Retention time: 2.58 minutes. ¹H NMR (400 MHz, DMSO) δ 10.92 (s,1H), 7.01 (s, 1H), 6.83 (s, 2H), 5.64 (s, 2H), 2.27 (s, 6H), 2.21 (s,3H), 1.20 (s, 9H).

Step 2:3-(tert-butyl)-4-methoxy-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxamide

5-tert-Butyl-N-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(200. mg, 0.388 mmol), anhydrous methanol (1.554 g, 1.965 mL, 48.50mmol), xylene (2.000 mL), diacetoxypalladium (8.711 mg, 0.03880 mmol),(diacetoxyiodo)benzene (374.9 mg, 1.164 mmol), and 4 A molecular sieveswere combined in a capped 10 mL vial. The mixture was heated in an oilbath to 100° C. for 40 hours. The mixture was allowed to cool wasdiluted with water, extracted three times with dichloromethane (10 mL),and, the combined organics were washed with a saturated aqueous sodiumbicarbonate solution and then a saturated aqueous solution of sodiumchloride. The organic layer was dried over sodium sulfate and thenpurified by silica gel column chromatography (24 g) utilizing a gradientof 0 to 50% ethyl acetate in hexanes to afford5-tert-butyl-4-methoxy-N-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(161 mg, 0.295 mmol, 76.1%) as an off-white solid. ESI-MS m./z talc.545.19135, found 546.2 (M+1)⁺; Retention time: 2.4 minutes. ¹H NMR (400MHz, DMSO) δ 10.76 (s, 1H), 6.83 (s, 2H), 5.39 (s, 2H), 3.79 (s, 3H),2.28 (s, 6H), 2.20 (s, 3H), 1.25 (s, 9H).

Step 3: Methyl3-(tert-butyl)-4-methoxy-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxylate

5-tert-butyl-4-methoxy-N-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(161 mg, 0.295 mmol) was dissolved in anhydrous tetrahydrofuran (3.220mL) and to the mixture was added (bis(trimethylsilyl)amino)lithium(442.7 μL of 1 M in tetrahydrofuran, 0.4427 mmol) at 0° C. and theresulting mixture was allowed to stir for 10 minutes. Then methylchloroformate (83.66 mg, 68.41 μL, 0.8853 mmol) was added and thereaction mixture was allowed to stir for one hour, and then concentratedunder reduced pressure. The residue was redissolved in anhydroustetrahydrofuran (3.220 mL) and then the mixture was cooled to 0° C. inan ice water bath. Sodium methoxide (319.0 μL of 25%w/v in methanol,1.476 mmol) was added and the reaction mixture was stirred for 10minutes. The mixture was diluted with water, extracted three times withethyl acetate (10mL) and the combined organics were washed with brine.The mixture was dried over sodium sulfate, and then purified byreverse-phase preparative chromatography utilizing a gradient from 10 to99% acetonitrile in water containing 5 mM aqueous hydrochloric acid toyield methyl3-(tert-butyl)-4-methoxy-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxylate(25.8 mg, 0.0749 mmol, 25.4%) as an off-white solid. ESI-MS tniz talc.344.21, found 345.2 (M+1)⁺; Retention time: 1.92 minutes.

Step 4:3-(tert-butyl)-4-methoxy-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxylicacid

To methyl3-(tert-butyl)-4-methoxy-1-(2,4,5-trimethylbenzyl)-1H-pyrazole-5-carboxylate(30. mg, 0.087 mmol) in anhydrous tetrahydrofuran (600.0 μL) was addedsodium hydroxide (108.94 of 4 M, 0.4355 mmol), the mixture was heated to70° C. and stirred for 3 hours. The mixture was allowed to cool and thenit was purified directly by reverse-phase preparative chromatographyutilizing a gradient from 10 to 99% acetonitrile in water containing 5mM aqueous hydrochloric acid to yield3-(tert-butyl)-4-methoxy-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxylicacid (27.3 mg, 0.0826 mmol, 95%) as an off-white solid. ESI-MS m/z calc.330.19434, found 331.2 (M+1)⁺; Retention time: 2.08 minutes.

PREPARATION 68:N-[amino-(6-amino-2-pyridyl)-oxo-$Î{6}-sulfanylidene]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 1602) (Compound 1481) (Compound 515) Step 1:2-fluoro-6-[(6-fluoropyridin-2-yl)disulfanyl]pyridine

A mixture of 2-fluoro-6-hydroxypyridine (1.13 g, 10.0 mmol) andphosphorus pentasulfide (4.44 g, 20.0 mmol) in toluene (50 mL) wasrefluxed for 18 hours. Once cooled, the flask was placed in an ice bathand quenched with water (50 mL) and then basified to a pH of about 8-9with 25% NaOH. The mixture was filtered over celite to remove somesolids that were still present and washed with water (50 mL) and ethylacetate (200 mL). The biphasic mixture was transferred to a 1.0-Lseparatory funnel, extracted and the layers were separated. The aqueouslayer was extracted again with ethyl acetate (100 mL), and the organiclayers were then combined, washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica-gel column chromatography, eluting from0% to 10% ethyl acetate in heptanes to afford2-fluoro-6-[(6-fluoropyridin-2-yl)disulfanyl]pyridine (304 mg, 23.7%yield) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): ppm 6.75 (ddd,J=8.0, 2.7, 0.5 Hz, 1H), 7.49 (ddd, J=7.7, 2.1, 0.6 Hz, 1H), 7.72 (q,J=7.9 Hz, 1H). [M+H]⁺=257.0.

Step 2:6-tert-butyl-N-[(6-fluoropyridin-2-yl)sulfinyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

To a solution of 2-fluoro-6-[(6-fluoropyridin-2-yl)disulfanyl]pyridine(744 mg, 2.90 mmol) and6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide (906 mg,2.90 mmol) in pyridine (10 mL) and acetonitrile (10 mL) was addedbromine (0.172 mL, 3.36 mmol) dropwise at 0° C. After complete addition,the mixture was stirred at room temperature overnight. Additionalbromine (0.087 mL, 1.7 mmol) was added at room temperature and themixture was stirred for an additional hour. Solvent was then removedunder reduced pressure and pyridine was further co-evaporated withtoluene (10 mL) two times under reduced pressure. The residue waspurified by silica gel column chromatography (24 g) column, eluting from0% to 25% ethyl acetate in heptane to afford6-tert-butyl-N-[(6-fluoropyridin-2-yl)sulfinyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(850 mg, 64% yield) as an off-white solid. ¹H NMR (300 MHz, CDCl₃): ppm1.08 (s, 9H), 2.00 (s, 6H), 2.29 (s, 3H), 6.86 (s, 2H), 7.03-7.89 (m,1H), 7.12 (d, J=8.0, 1H), 7.99-8.11 (m, 2H), 8.53 (d, J=8.0 Hz, 1H). ‘⁹FNMR (282 MHz, CDCl₃): ppm−64.8 (s, 1 F). [M+H]⁺=456.1.

Step 3:6-(tert-butyl)-N-(6-fluoropyridine-2-sulfonimidoyl)-2-(mesityloxy)nicatinamide

To a solution of6-tert-butyl-N-[(6-fluoropyridin-2-yl)sulfinyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(419 mg, 0.920 mmol) in dichloromethane (10 mL) was added tert-butylhypochlorite (94.8 μL, 0.87 mmol) at 0° C. The mixture was stirred atthis temperature for 2 days. The solvent was then removed under reducedpressure at below 21° C. The crude product was used directly in the nextstep without further purification. The residue was dissolved inacetonitrile (11 mL) then hexamethyldisilazane (1.09 mL, 5.22 mmol) wasadded at 0° C. The mixture was stirred for 1 hour at room temperaturethen quenched by the addition of water (3 mL). The mixture was extractedwith ethyl acetate (2×20 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography column (24g), eluting from 0% to 5% methanolin dichloromethane, to afford6-(tert-butyl)-N-(6-fluoropyridine-2-sulfonimidoyl)-2-(mesityloxy)nicotinamide(286 mg, 70% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃): ppm 1.08(s, 9H), 2.03 (s, 6H), 2.29 (s, 3H), 6.84 (s, 2H), 6.97 (d, J=8.0 Hz,1H), 7.16 (ddd, J=8.0, 2.6, 0.8 Hz, 1H), 7.94-8.11 (m, 2H), 8.35 (d,J=8.0 Hz, 1H). ¹⁹F NMR (282 MHz, CDCl₃): ppm−64.1 (s, 1 F).[M+H]⁺=471.1.

Step 4:6-(tert-butyl)-N-(6-((2,4-dimethoxybenzyl)amino)pyridine-2-sulfonimildayl)-2-(mesityloxy)nicotinamide

A mixture of6-(tert-butyl)-N-(6-((2,4-dimethoxybenzyl)amino)pyridine-2-sulfonimidoyl)-2-(mesityloxy)nicotinamide(400. mg, 0.850 mmol), 2,4-dimethoxybenzylamine (0.25 mL, 1.7 mmol) andtriethylamine (0.24 mL, 1.7 mmol) in dimethylsulfoxide (10 mL) wasstirred at 100° C. overnight. After completion, the mixture was dilutedwith ethyl acetate (20 mL), washed with brine (2×10 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by reverse-phase column chromatography on a 25 gcolumn, eluting from 0% to 100% acetonitrile in water containing 0.1%formic acid to afford6-(tert-butyl)-N-(6-((2,4-dimethoxybenzypamino)pyridine-2-sulfonimidoyl)-2-(mesityloxy)nicotinamide(426 mg, 81.1% yield) as a yellow foam. ¹HNMR (300 MHz, CDCl₃): ppm 1.07(s, 9H), 2.03 (s, 6H), 2.27 (s, 3H), 3.77 (s, 3H), 3.82 (s, 3H), 4.42(s, 2H), 5.18-5.35 (br. s., 1H), 6.36 (dd, J=8.3, 2.3 Hz, 1H), 6.45 (d,J=2.3 Hz, 1H), 6.52 (d, J=8.3 Hz, 1H), 6.81 (s, 2H), 6.94 (d, J=7.9 Hz,1H), 7.18 (d, J=8.3 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.45 (dd, J=8.5,7.4 Hz, 1H), 8.38 (d, J=7.9 Hz, 1H). [M+H]⁺=618.2.

Step 5:N-(6-aminopyridine-2-sulfonimidoyl)-6-(tert-butyl)-2-(mesityloxy)nicotinamide

To a stirred solution ofN-[amino(6-{[(2,4-dimethoxyphenyl)methyl]amino}pyridin-2-yl)oxo-λ⁶-sulfanylidene]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(420 mg, 0.68 mmol) in dichloromethane (50 mL) was added trifluoroaceticacid (12 mL) and the mixture was stirred until LCMS indicatedcompletion. The reaction mixture was diluted with dichloromethane (20mL) and water (20 mL) and the pH was adjusted to greater than 6 byadding solid NaHCO₃. The mixture was extracted with dichloromethane(2×20 mL) and the combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by reverse-phase column chromatography on a 25 g column,eluting from 0% to 100% acetonitrile in water containing 0.1% formicacid to affordN-(6-aminopyridine-2-sulfonimidoyl)-6-(tert-butyl)-2-(mesityloxy)nicotinamide(90. mg, 28% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃+5 drops ofDMSO-d₆) ppm 0.96 (s, 9H), 1.90 (s, 6H), 2.17 (s, 3H), 5.78 (br. s.,2H), 6.59 (d, J=8.2 Hz, 1H), 6.71 (s, 2H), 6.82 (d, J=7.8 Hz, 1H),7.19-7.31 (m, 3H), 7.36-7.47 (m, 1H), 8.15 (d, J=7.8 Hz, 1H).[M+H⁺=468.1.

Step 6:N-[(S)-amino(6-aminopyridin-2-yl)oxo-λ⁶-sulfanylidene]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamideandN-[(R)-amino(6-aminopyridin-2-yl)oxo-λ⁶-sulfanylidene]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide

N-(6-aminopyridine-2-sulfonimidoyl)-6-(tert-butyl)-2-(mesityloxy)nicotinamidewas dissolved in a methanol and dimethylsulfoxide mixture (4:1 (v/v)) toan approximate concentration of 16 mg/mL. The solution was subjected tochiral SFC (70 μL injections; column: Chiralpak. OD-H (250×21.2 mm), 5μm; mobile phase: 20% methanol, 80% CO₂; flow: 10.0 mL/min) to giveN-[(S)-amino(6-aminopyridin-2-yl)oxo-λ⁶-sulfanylidene]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(peak. 1, enantiomer 1, 98% ee), andN-[(R)-amino(6-aminopyridin-2-yl)oxo-λ⁶-sulfanylidene]-6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(peak 2, enantiomer 2, 97.3% ee). Absolute stereochemistry is inknown.

PREPARATION 69: (R)-1-(2,4,6-trimethylbenzyl)indoline-2-carboxylic acid

A suspension of (R)-indoline-2-carboxylic acid (300. mg, 1.84 mmol) andpotassium hydroxide (309.5 mg, 5.517 mmol) was stirred in isopropanol(2.010 mL) for 20 minutes. The reaction mixture was stirred for 20minutes and was treated with 2-(chloromethyl)-1,3,5-trimethyl-benzene(341.2 mg, 2.023 mmol). The reaction mixture was stirred overnight. Thereaction mixture was diluted with ethyl acetate and water. The mixturewas extracted with ethyl acetate and the aqueous layer was acidified topH 5 and extracted again with ethyl acetate. The combined organics werewashed with water, brine, dried over sodium sulfate, filtered andconcentrated to yield (R)-1-(2,4,6-trimethylbenzyl)indoline-2-carboxylicacid (220. mg, 0.745 mmol, 40.5%) as a white solid. ESI-MS m/z calc.295.15723, found 296.5 (M+1)⁺; Retention time: 1.79 minutes.

PREPARATION 70: tert-butyl2,3,4,5-tetrahydro-1H-1-benzazepine-2-carboxylate Step 1:3-(2-bromophenyl)propan-1-ol

A solution of 3-(2-bromophenyl)propanoic acid (1.0 g, 4.4 mmol) inanhydrous tetrahydrofuran (5.0 mL) was treated withborane-tetrahydrofuran complex in tetrahydrofuran (1.0 M, 7.0 mL, 7.0mmol) at 0° C. over a period of 15 minutes. The mixture was stirred at0° C. for an additional 1 hour. After completion, the residual boranewas quenched by the cautious addition of water (1 mL) and the solventwas removed under vacuum. The resulting residue was dissolved in ether(20 mL) and the organic layer was washed with water (20 mL), brine (20mL), dried over sodium sulfate, filtered, and concentrated underpressure to afford 3-(2-bromophenyl)propan-1-ol as a colorless oil (938mg, quantitative yield). This compound was used in the following stepwithout further purification.

Step 2: Synthesis of 1-bromo-2-(3-bromopropyl)benzene

To a solution of 3-(2-bromophenyl)propan-1-ol (938 mg, 4.36 mmol) andtriphenylphosphine (2.29 g, 8.72 mmol) in anhydrous dichloromethane (25mL) was added N-bromosuccinimide (1.63 g, 9.16 mmol) at 0° C. and themixture was stirred at room temperature for 2 hours. After completion,the reaction was quenched by the addition of water (20 mL) and theorganic layer was separated and dried over sodium sulfate, filtered andconcentrated under pressure. The residue was purified by silica gelchromatography (40 g), eluting from 0% to 10% ethyl acetate in heptanesto afford 1-bromo-2(3-bromopropyl)benzene as a yellow oil (830 mg, 68.5%yield).¹H NMR (300 MHz, CDCl₃) ppm 2.13-2.24 (m, 2H), 2.90 (t, J=7.7 Hz,2H), 3.43 (t, J=6.5 Hz, 2H), 7.04-7.12 (m, 1H), 7.20-7.28 (m, 2H), 7.54(d, J=7.7 Hz, 1H). [M+H]⁺=279.1.

Step 3: tert-butyl 2-amino-5-(2-bromophenyl)pentanoate

To a suspension of potassium hydroxide (1.27 g, 22.6 mmol) indimethylsulfoxide (10 mL) cooled in a cold water bath was addedN-(diphenylmethylene)glycine tert-butyl ester (2.23 g, 7.55 mmol). Then,1-bromo-2-(3-bromopropyl)benzene (938 mg, 4.36 mmol) in dimethylsulfoxide (10 mL) was added dropwise and the mixture was stirred at roomtemperature for 1 hour. After completion, the mixture was diluted withethyl acetate (100 mL) and the solution was filtered. The mixture waswashed with water (3×50 mL), brine, dried over sodium sulfate, filtered,and concentrated under reduced pressure. After drying under high vacuum,the residue was dissolved in tetrahydrofuran (78 mL). To this solutionwas added 1 N HCl (75.7 mL, 75.7 mmol) dropwise at 0° C. and the mixturewas stirred at this temperature for an additional 2 hours. The resultingmixture was then neutralized by addition of solid sodium bicarbonate andextracted with dichloromethane (100 mL). The organic layer was driedover sodium sulfate, filtered and concentrated under pressure. Theresidue was purified by silica gel chromatography (80 g) eluting from 0%to 10% ethyl acetate in heptanes to afford tert-butyl2-amino-5-(2-bromophenyl)pentanoate as a yellow oil (2.21 g, 86.4% yieldover two steps).¹H NMR (300 MHz, CDCl₃) ppm 1.45 (s, 9H), 1.60-1.81 (m,2H), 2.70-2.78 (m, 2H), 3.33-3.39 (m, 2H), 7.00-7.09 (m, 1H), 7.18-7.24(m, 2H), 7.51 (d, J=8.1 Hz, 1H). [M+H]⁺=328.1.

Step 4: tert-butyl 2,3,4,5-tetrahydro-1H-1-benzazepine-2-carboxylate

A mixture of tert-butyl 2-amino-5-(2-bromophenyl)pentanoate (1.7 g, 5.2mmol), palladium acetate (116 mg, 0.518 mmol), triphenylphosphine (408mg, 1.55 mmol), and cesium carbonate (3.4 g, 10. mmol) in toluene (80mL) was stirred at 110° C. overnight. After completion, the mixture wasdiluted with ethyl acetate (100 mL) and washed with water (50 mL), brine(50 mL), dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by silica gel chromatography(80 g) eluting from 0% to 20% ethyl acetate in heptanes to affordtert-butyl 2,3,4,5-tetrahydro-1H-1-benzazepine-2-carboxylate as a yellowoil (527 mg, 41.0%). ¹HNMR (300 MHz, CDCl₃) ppm 1.46-1.57 (m, 10H),1.66-1.82 (m, 1H), 1.94-2.08 (m, 1H), 2.24-2.36 (m, 1H), 2.65-2.77 (m,1H), 2.78-2.91 (m, 1H), 3.44 (dd, J=10.7, 2.3 Hz, 1H), 4.50 (br. s, 1H),6.79-6.88 (m,2H), 7.01-7.11 (m, 2H). [M+H]⁺=248.2

PREPARATION 71:5-ethyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[2,3-b]pyridine-2-carboxylate

A solution of methyl5-bromo-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[2,3-b]pyridine-2-carboxylate(150. mg, 0.387 mmol),1,2-dimethoxyethane (1.35 mL)4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (119.3 mg, 0.7746 mmol),and potassium carbonate (187.4 mg, 1.356 mmol) in 1,2-dimethoxyethane(1.35 mL) and water (0.45 mL) was degassed and put under nitrogen. Thereaction mixture was treated with tetrakis(triphenylphosphine)palladium(0) (44.75 mg, 0.03873 mmol) and irradiated in a microwave reactor at120° C. for 30 minutes. The mixture was diluted with water and extractedthree times with ethyl acetate. The combined organics were washed withbrine, dried oer sodium sulfate, filtered, and concentrated underreduced pressure. The resulting crude methyl1-[(2,4,6-trimethylphenyl)methyl]-5-vinyl-pyrrolo[2,3-b]pyridine-2-carboxylatewas dissolved in methanol (12.45 mL) and put under a nitrogen atmospherebefore being treated with wet 10% palladium on carbon (41.22 mg, 0.03873mmol). The mixture was evacuated and put under a hydrogen atmosphere for16 hours. The reaction mixture was put under a nitrogen atmosphere andfiltered through celite to afford the crude product which was purifiedon 12 g of silica gel utilizing a gradient of 0-40% ethyl acetate inhexanes to yield methyl5-ethyl-1-[(2,4,6-trimethylphenyl)methyl]pyrrolo[2,3-b]pyridine-2-carboxylateESI-MS m/z calc. 336.18378, found 337.5 (M+1)⁺; Retention time: 2.24minutes.

PREPARATION 72 Step 1: Synthesis of 2-(2-bromophenyl)propan-2-amine

Methylmagnesium bromide (54.9 mL, 164.8 mmol, 3M in diethyl ether) wasadded to a solution of 2-bromobenzonitrile (10.0 g, 54.9 mmol) indiethyl ether (200 mL) and the reaction mixture was stirred at roomtemperature under nitrogen. After 30 minutes, titanium isopropoxide(16.3 mL, 54.9 mmol) was added and resulting mixture was refluxedovernight. Once cooled to 0° C., 2N NaOH (400 mL) was added andresulting mixture was stirred at room temperature for 30 minutes. Thesolution was diluted with saturated aqueous sodium bicarbonate (400 mL),extracted using methyl tert-butyl ether (3×200 mL). The organic layerswere combined and concentrated under reduced pressure. The residue wasdissolved in 1N hydrochloric acid (75 mL) and washed with methyltert-butyl ether (150 mL). The aqueous layer was basified to pH 10-11using 2N sodium hydroxide and the resulting solution was extracted withmethyl tert-butyl ether (3×200 mL). The organic layers were combined,dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford 2-(2-bromophenyl)propan-2-amine (9.0 g, 77% yield) asorange oil. ¹H NMR (300 MHz, CDCl₃): ppm 1.66 (s, 6H), 7.02-7.10 (m,1H), 7.13-7.43 (m, 1H), 7.55-7.61 (m, 2H). [M+H]⁺=214.0.

Step 2: Synthesis of tert-butyl2-{[2-(2-bromophenyppropan-2-yl]amino}acetate

tert-Butyl 2-bromoacetate (6.24 mL, 42.2 mmol) was slowly added to asolution of 2-(2-biomophenyl)propan-2-amine (9.04 g, 42.22 mmol) andpotassium carbonate (14.6 g, 105.6 mmol) in dry tetrahydrofuran (100 mL)at 0° C. and reaction mixture was stirred at 50-55° C. for 16 hours.Once cooled to room temperature, reaction mixture was diluted with brine(100 mL) and extracted using ethyl acetate (3×100 mL). The organiclayers were combined, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting from 0% to 20% ethyl acetate in heptanes toafford tert-butyl 2-{[2-(2-bromophenyl)propan-2-yl]amino}acetate (4.5 g,32% yield) as a yellow oil. NMR (300 MHz, CDCl₃) ppm 1.43 (s, 9H), 1.63(s, 6H), 2.94 (s, 2H), 7.09 (dt, J=7.6, 1.7 Hz, 1H), 7.22-7.31 (m, 1H),7.43 (dd, J=7.9, 1.6 Hz, 1H), 7.58 (dd, J=7.9, 1.4 Hz, 1H).[M+H]⁺=328.1.

Step 3: tert-butyl2-1[(benzyloxy)carbonyl][2-(2-bromophenyl)propan-2-yl]amino}acetate

Diisopropylethylamine (5.48 mL, 31.4 mmol) was added to a solution oftert-butyl 2-([2-(2-bromophenyl)propan-2-yl]amino}acetate (4.48 g, 13.7mmol) in dichloromethane (50 mL) and solution was cooled to 0° C. Benzylchloroformate (3.51 mL, 24.6 mmol) was added dropwise at 0° C. andreaction mixture was stirred at room temperature overnight. The reactionmixture was diluted with dichloromethane (50 mL) and washed with 5%aqueous citric acid (2×50 mL) and brine (50 mL). The organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography, elutingfrom 0% to 10% ethyl acetate in heptane to afford tert-butyl2-{[(benzyloxy)carbonyl][2-(2-bromophenyppropan-2-yl]amino}acetate (4.2g, 67% yield) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): ppm 1.41 (s,6H), 1.55 (s, 3H), 1.78 (s, 2H), 1.84 (s, 4H), 4.21 (s, 1.3H), 4.32 (s,0.7H), 4.83 (s, 0.7H), 4.99 (s, 1.3H), 6.70-7.62 (m, 9H). [M+H]⁺=484.1.

Step 4: 2-benzyl 1-tert-butyl3,3-dimethyl-2,3-dihydro41H-isoindole-1,2-dicarboxylate

Tris(dibenzylideneacetone)dipalladium(0) (87 mg, 0.10 mmol),2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)-2-amine(PhDavePhos) (73 mg, 0.19 mmol) and lithium tort-butoxide (0.31 g, 3.81mmol) were added in order to a solution of tert-butyl2-([(benzyloxy)carbonyl][2-(2-bromophenyl)propan-2-yl]amino}acetate(0.88 g, 1.90 mmol) in dioxane (10 mL) previously degased and purgedwith nitrogen. The reaction mixture was stirred at 90° C. overnight.Once cooled at room temperature, the reaction mixture was diluted withethyl acetate (20 mL), filtered and concentrated under reduced pressure.The residue was purified by silica gel chromatography, eluting from 0%to 10% ethyl acetate in heptane to afford 2-benzyl 1-tert-butyl3,3-dimethyl-2,3-dihydro-1H-isoindole-1,2-dicarboxylate (0.31 g, 43%yield) as an orange oil. ¹H NMR (300 MHz, CDCl₁): ppm 1.31 (s, 6H), 1.45(s, 3H), 1.65 (s, 1H), 1.73 (s, 1H), 1.76 (s, 2H), 1.81 (s, 2H),5.11-5.47 (m, 3H), 7.12-7.48 (m, 9H). [M+Na]⁺=404.2.

PREPARATION 73:6-hydroxy-1-methyl-N-((6-nitropyridin-2-yl)sulfony)-2-(2,4,6-trimethylbenzyl)isoindoline-1-carboxamide

Under an atmosphere of nitrogen,6-methoxy-1-methyl-N-[(6-nitro-2-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(333 mg, 0.635 mmol) was dissolved in dichloromethane (30 mL). Themixture was cooled to −78° C., and tribromoborane (5.046 g, 1.904 mL of1 M, 1.904 mmol) was added to the reaction mixture dropwise. The mixturewas slowly warmed to room temperature and stirred for 16 hours. Thereaction mixture was added to approximately 50 mL of ice. The layerswere separated, and the aqueous layer was extracted with dichloromethane(3×5 mL). The combined organic layers were dried over sodium sulfate,concentrated, and purified on a column of silica gel utilizing agradient of 0 to 100% ethyl acetate in hexanes to yield6-hydroxy-1-methyl-N-[(6-nitro-2-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]isoindoline-1-carboxamide(90.7 mg, 0.178 mmol, 28.0%) ESI-MS m/z calc. 510.15732, found 511.5(M+1)⁺; Retention time: 0.56 minutes

PREPARATION 74: tert-butyl2,3,4,5-tetrahydro-1H-benzo[c]azepine-3-carboxylate Step 1: 3,4-dihydro-1H-2-benzopyran-1-one

To a solution of isochroman (15.0 g, 112 mmol) in dichloromethane (1.4L) stirred at room temperature was added, over 15 minutes, a homogeneousmixture of potassium permanganate (106 g, 672 mmol) and manganesedioxide (58.0 g, 672 mmol), prepared by grinding potassium permanganateand then mixing with manganese dioxide using a pestle and mortar. Thesuspension was vigorously stirred for 4 days at room temperature, andthen filtered through a pad of Celite. The filtrate was concentrated andthe residue was purified by silica chromatography, eluting with amixture of heptanes and ethyl acetate (0 to 20%) to provide3,4-dihydro-1H-2-benzopyran-1-one (8.2 g, 49% yield) as a colorless oil.¹H NMR (CDCl₃, 300 MHz) ppm 3.06 (t, J=6.0 Hz, 2H), 4.52 (t, J=6.0 Hz,2H), 7.20-7.30 (m, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H),8.06 (d, J=7.6 Hz, 1H).

Step 2: ethyl 2-(2-bromoethyl)benzoate

Phosphorus tribromide (1.05 mL, 11.0 mmol) and bromine (0.62 mL, 12mmol) were slowly added to a solution of3,4-dihydro-1H-2-benzopyran-1-one (1.5 g, 10. mmol) in carbontetrachloride (15 mL) cooled in an ice-water bath. The mixture was thenstirred at room temperature for 16 hours. The resulting orangesuspension was stirred at 60° C. for 3 hours. The red mixture was thencooled down and ethanol (10 mL) was slowly added at 0° C. (exothermic!).The reaction mixture (orange solution) was stirred for one hour. Thereaction mixture was partitioned between dichloromethane (50 mL) andwater (20 mL). The organic phase was separated and washed with brine (10mL), dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by silica chromatography, eluting with amixture of ethyl acetate and heptanes (0 to 10%) to afford ethyl2-(2-bromoethyl)benzoate (2.0 g, 78% yield) as a pale yellow oil. ¹H NMR(300 MHz, CDCl₃) ppm 1.41 (t, J=6.9 Hz, 3H), 3.50 (t, J=6.9 Hz, 2H),3.64 (t, J=6.9 Hz, 2H), 4.38 (q, J=6.9 Hz, 2H), 7.27-7.39 (m, 2H), 7.45(t, J=7.5 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H).

Step 3: ethyl 2-(3-amino-4-ethoxy-4-oxobutyl)benzoate

The reaction was run in two separate batches.

N-(Diphenylmethylene)glycine ethyl ester (4.17 g, 15.6 mmol) was addedto a suspension of finely powdered potassium hydroxide (2.63 g, 46.8mmol) in dimethylsulfoxide (20 ml) cooled with an ice-water bath (anorange mixture was obtained). Then ethyl 2-(2-bromoethyl)benzoate (4.0g, 15.6 mmol) was added dropwise. The reaction was stirred at roomtemperature for 60 minutes and then diluted with ethyl acetate (150 mL).The solution was decanted into a separation funnel and the solid (KOH)was discarded. The organic phase was washed with water (3×50 mL,) brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thesecond batch was run in a similar way: ethyl 2-(2-bromoethyl) benzoate(9.3 g, 36.1 mmol), N-(diphenylmethylene)glycine ethyl ester (9.65 g,36.1 mmol), potassium hydroxide (6.08 g, 108.3 mmol) anddimethylsulfoxide (50 mL).

The crude products of the two batches were combined (19 g) and dissolvedin tetrahydrofuran (50 mL). The solution was cooled with an ice-waterbath and 1 N HCl aqueous solution (60 mL) was added. The mixture wasstirred at room temperature for 30 minutes. Water (50 mL) and ethylacetate (50 mL) were added, the biphasic mixture was extracted and thetwo phases were separated. The aqueous phase was then basified with 2 NNaOH aqueous solution (30 mL) at 0° C. and the resulting aqueoussolution was extracted with ethyl acetate (2×50 mL). The organic layerswere combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The residue was purified withsilica chromatography, eluting with a mixture of methanol anddichloromethane (0-7%) to give ethyl2-(3-amino-4-ethoxy-4-oxobutyl)benzoate (6.6 g, 46% yield) as a yellowoil. ¹H NMR (300 MHz, CDCl₃) 1.27 (t, J=7.1 Hz, 3H), 1.41 (t, J=7.1 Hz,3H), 1.75-1.93 (m, 1H), 1.97-2.14 (m, 1H), 2.95-3.15 (m, 2H), 3.42-3.54(m, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 7.20-7.30 (m,2H), 7.41 (t, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H). LCMS: [M+H]⁺=280.2.

Step 4: Synthesis of ethyl1-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-3-carboxylate

Sodium metal (823 mg, 35.8 mmol) was added to anhydrous ethanol (270 mL,dried with 3 Å molecular sieves) in a flask at room temperature. Themixture was stirred at room temperature until all the sodium haddisappeared. Then a solution of ethyl2-(3-amino-4-ethoxy-4-oxobutyl)benzoate (5.0 g, 18 mmol) in anhydrousethanol (30 mL) was added at room temperature. The reaction was stirredat room temperature for two days and then cooled with an ice-water bath.Thionyl chloride (10 mL) was slowly added (reacts violently) and thereaction was refluxed for 2 hours. The solvent was removed under reducedpressure and the residue was taken up into ethyl acetate (100 mL),washed with saturated aqueous sodium bicarbonate (30 mL), brine, driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by silica chromatography, eluting with a mixture of ethylacetate and heptanes (10 to 100%) to afford ethyl1-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-3-carboxylate (2.9 g, 69%yield) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) ppm 1.24 (t, J=6.7 Hz,3H), 2.07-2.25 (m, 1H), 2.26-2.43 (m, 1H), 2.70-2.84 (m, 1H), 2.89-3.08(m, 1H), 3.80-3.95 (m, 1H), 4.20 (q, J=6.7 Hz, 2H), 6.69 (s, 1H), 7.20(d, J=7.2 Hz, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.70(d, J=7.2 Hz, 1H). LCMS: [M+H]⁺=234.1.

Step 5: tert-butyl1-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-3-carboxylate

Butyl lithium (17.4 mL of 2.5 M in hexanes, 43.4 mmol) was added to asolution of anhydrous tert-butanol (4.7 mL, 50. mmol, distilled and thendried over potassium carbonate) in anhydrous tetrahydrofuran (40 mL) at−78° C. in a pressure tube under nitrogen. The mixture was stirred atroom temperature for 10 min, then a solution of ethyl1-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-3-carboxylate (2.9 g, 12 mmol)in anhydrous tetrahydrofuran (10 mL) was added and the mixture wasstirred at 30° C. overnight. Volatiles were removed under reducedpressure and the residue was taken up into a mixture of water (40 mL)and dichloromethane (100 mL). The two phases were separated and theorganic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica chromatography,eluting with a mixture of ethyl acetate and heptanes (0 to 30%) to givetert-butyl 1-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-3-carboxylate (1.4g, 43% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) ppm 1.44 (s,9H), 1.99-2.23 (m, 1H), 2.32 (tt, J=12.7, 6.3 Hz, 1H), 2.77 (dd, J=13.7,6.3 Hz, 1H), 2.89-3.11 (m, 1H), 3.68-3.88 (m, 1H), 6.64 (br. s., 1H),7.21 (d, J=7.3 Hz, 1H), 7.29-7.49 (m, 2H), 7.71 (d, J=7.5 Hz, 1H).[M+H]⁺=262.1.

Step 6: tert-butyl 1-methoxy-4,5-dihydro-1H-2-benzazepine-3-carboxylate

The reaction was run in two identical batches. 4 A molecular sieves wereadded to a sealed tube. The tube was flame-dried under vacuum and thenflushed with nitrogen. After the tube was cooled to room temperature,tert-butyl 1-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-3-carboxylate (522mg, 2.00 mmol) was added followed by anhydrous dichloromethane (9 mL)and trimethyloxonium tetrafluoroborate (296 mg, 2.00 mmol). The mixturewas stirred at 30° C. for 16 hours. The mixture was quenched with asaturated aqueous sodium bicarbonate solution (30 mL). The resultingmixture was extracted with ethyl acetate (2×40 mL). The organic phaseswere combined and washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The residue of the two batcheswere combined and purified by silica chromatography, eluting with amixture of ethyl acetate and heptanes (0 to 30%) to provide tert-butyl1-methoxy-4,5-dihydro-3H-2-benzazepine-3-carboxylate (900. mg, 3.27mmol, 81.7% yield) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) ppm 1.43(s, 9H), 2.33-2.49 (m, 2H), 2.58-2.70 (m, 2H), 3.50 (dd, J=11.0, 7.2 Hz,1H), 3.96 (s, 3H), 7.20-7.28 (m, 1H), 7.30-7.40 (m, 2H), 7.41-7.47 (m,1H). LCMS: [M+H]⁺=276.1.

l Step 7: tert-butyl 2,3,4,5-tetrahydro-1H-2-benzazepine-3-carboxylate

Sodium cyanoborohydride (821 mg, 13.1 mmol) was added to a solution oftert-butyl 1-methoxy-4,5-dihydro-3H-2-benzazepine-3-carboxylate (900.mg, 3.27 mmol) in acetic acid (3 mL) at 0° C. The mixture was stirred atroom temperature for 2 hours. The mixture was diluted with ethyl acetate(40 mL) and cooled with an ice-water bath. An aqueous solution of NaOH(25% w/v) was slowly added to adjust the pH to about 8. The two phaseswere separated and the aqueous phase was extracted with ethyl acetate(40 mL). The organic phases were combined, washed with brine (10 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica chromatography, eluting with a mixture ofethyl acetate and dichloromethane (0 to 50%) to give tert-butyl2,3,4,5-tetrahydro-1H-2-benzazepine-3-carboxylate (610. mg, 2.47 mmol,75.5% yield) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) ppm 1.46 (s, 9H),1.53-1.66 (m, 1H), 2.17-2.37 (m, 1H), 2.79-2.99 (in, 1H), 2.99-3.18 (m,1H), 3.65 (dd, J=10.6, 2.9 Hz, 1H), 3.93 (d, J=15.1 Hz, 1H), 3.97 (d,J=15.1 Hz, 1H), 7.06-7.21 (m, 4H). [M+H]⁺=248.1.

PREPARATION 75:1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidine-3-sulfonamide Step 1:2,4-dibromo-N-[(4-methoxyphenyl)methyl]butanamide

To a solution of 2,4-dibromobutanoyl chloride (5.00 g, 18.9 mmol) indichloromethane (250 mL) at 0° C. was added triethylamine (2.38 g, 23.6mmol) followed by 4-methoxybenzylamine (2.59 g, 18.9 mmol) and themixture was stirred at 0° C. for 2 hours. The reaction was then pouredat 0° C. into a solution of 5% citric acid (80 mL) at pH=3-4 and dilutedwith dichloromethane (100 mL) and water (50 mL). The organic layer wasseparated and the aqueous player was extracted again withdichloromethane (50 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford crude2,4-dibromo-N-[(4-methoxyphenyl)methylibutanamide (7.09 g, 103%) as abrown solid. ¹H NMR (300 MHz, CDCl₃) ppm 2.41-2.55 (m, 1H), 2.64-2.84(m, 1H), 3.52-3.61 (m, 2H), 3.80 (s, 3H), 4.36-4.44 (m, 2H), 4.55 (dd,J=9.0, 4.8 Hz, 1H), 6.54 (br. s, 1H), 6.85-6.91 (m, 2H), 7.19-7.23 (m,2H). [M+H⁺=366.0.

Step 2: 3-bromo-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one

To a solution of 2,4-dibromo-N-[(4-methoxyphenyl)methyl]butanamide (3.25g, 8.90 mmol) in tetrahydrofuran (120 mL) and N,N-dimethylforrnamide (12mL) was added sodium hydride (427 mg of 60% dispersion in mineral oil,17.8 mmol) portionwise at 0° C. and the mixture was stirred at roomtemperature for 2.5 hours. The reaction mixture was cooled again to 0°C. and quenched carefully with an aqueous 5% citric acid solution (10mL). The volatiles were then removed under reduced pressure. Thereaction mixture was diluted with water and dichloromethane and theaqueous layer was extracted twice with dichloromethane. The combinedorganic layers were dried over Na₂SO₄, filtered, concentrated underreduced pressure and co-evaporated with heptanes as a co-solvent (twice)to afford crude 3-bromo-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one (2.5g, 99%) as a pale yellow oil. ¹H NMR (300 MHz, CDCl₃) ppm 2.22-2.32 (m,1H), 2.47-2.60 (m, 1H), 3.14-3.21 (m, 1H), 3.35-3.44 (m, 1H), 3.80 (s,3H), 4.33-4.52 (m, 3H), 6.84-6.87 (m, 2H), 7.15-7.20 (m, 2H).[M+H]⁺=284.0.

Step 3: methyl3-({1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidin-3-yl}sulfonyl)propanoate

To a solution of 3-bromo-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one(2.50 g, 8.80 mmol) in dimethylsulfoxide (50 mL) was added sodium1-methyl 3-sulfinopropanoate (1.53 g, 8.80 mmol) and the reaction wasstirred at room temperature for three days. The solution was dilutedwith water (400 mL) and extracted with dichloromethane (2×250 mL). Thecombined organic layer was washed with water (150 mL), brine (100 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toafford crude methyl3-({1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidin-3-yl}sulfonyl)propanoate(2.5 g, 80.% yield). ¹H NMR (300 MHz, CDCl₃) ppm 2.31-2.45 (m, 1H),2.65-2.75 (m, 1H), 2.85-3.05 (m, 2H), 3.26 (dt, J=9.4, 3.8 Hz, 1H),3.41-3.50 (m, 1H), 3.74 (s, 3H), 3.79 (s, 3H), 3.77-3.92 (m, 2H), 4.01(dd, J=10.2, 4.6 Hz, 1H), 4.44 (s, 2H), 6.87 (d, J=8.6 Hz, 2H), 7.16 (d,J=8.5 Hz, 2H). [M+H]⁺=356.1.

Step 4: sodium 1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidine-3-sulfinate

To a solution of methyl3-((1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidin-3-yl}sulfonyppropanoate(2.50 g, 7.03 mmol) in a 1:1 (v/v) mixture of tetrahydrofuran andmethanol (40 mL) was added sodium methoxide (3.39 mL of 25 wt. % inmethanol, 14.8 mmol) and the reaction was stirred at room temperaturefor 4 hours. The reaction mixture was then concentrated under reducedpressure to remove the methyl acrylate and kept under reduced pressureto provide crude sodium1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidine-3-sulfinate that was useddirectly in the next step without further purification [M₊H]⁺=270.0(sulfinic acid).

Step 5: Synthesis of1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidine-3-sulfonamide

To a solution of crude sodium1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidine-3-sulfinate (2.05 g, 7.03mmol) in dimethylsulfoxide (20 ml) was added a solution ofhydroxylamine-O-sulfonic acid (3.98 g, 35.2 mmol) and sodium acetate(2.19 g, 26.7 mmol) in water (7 mL) at 0° C. The reaction was stirredfor 16 hours at room temperature then diluted with ethyl acetate andwater. The aqueous layer was extracted with ethyl acetate (2×100 mL).The combined organic layer was washed with brine (75 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by silica-gel chromatography using 0% to 10%methanol in dichloromethane (containing 1% NH₄OH) to afford1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidine-3-sulfonamide (1.3 g, 63%yield) as a pale brown solid. ¹H NMR (300MHz, CDCl₃) ppm 2.29-2.73 (m,2H), 3.14-3.34 (m, 1H), 3.34-3.51 (m, 1H), 3.80 (s, 3H), 3.89-4.11 (m,1H), 4.30-4.61 (m, 2H), 5.25 (br. s., 2H), 6.75-6.98 (m, 2H), 7.10-7.22(m, 2H). [M+H⁺=285.1.

PREPARATION 76:6-(3-fluoro-5-isobutoxy-phenyl)-N-(2-oxopyrrolidin-3-yl)sulfonyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 466)

6-(3-fluoro-5-isobutoxy-phenyl)-N-[1-[(4-methoxyphenyl)methyl[-2-oxo-pyrrolidin-3-yl]sulfonyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(32.7 mg, 0.0490 mmol) was dissolved in a mixture of trifluoroaceticacid (0.9319 mL) and dichloromethane (0.9319 mL).Trifluoromethanesulfonic acid (25.75 mg, 15.18 μL, 0.1716 mmol) was thenadded and the mixture and stirred at ambient temperature for 20 hours.The reaction mixture was concentrated, then diluted withdimethylsulfoxide and purified by reverese-phase chromatographyutilizing a C18 column and a gradient of 1-99% acetonitrile in 5 mM aqHCl to yield6-(3-fluoro-5-isobutoxy-phenyl)-N-(2-oxopyrrolidin-3-yl)sulfonyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 466) ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=19.3 Hz, 1H), 7.94(d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=10.1Hz, 1H), 7.28 (dd, J=14.4, 8.0 Hz, 1H), 6.90 (dt, J=10.6, 2.3 Hz, 1H),4.61-4.44 (m, 1H), 3.84 (d, J=6.7 Hz, 2H), 3.40-2.86 (m, 4H), 2.16-1.91(m, 2H), 1.71-1.60 (m, 7H), 1.60-1.49 (m, 1H), 1.16 (s, 1H), 1.06-0.96(m, 10H). ESI-MS m/z talc. 546.2312, found 547.3 (M+1)⁺; Retention time:1.87 minutes

PREPARATION 77:5-isopropyl-1-(2,4,6-trimethylbenzyl)-1H-indole-2-carboxylic acid and5-propyl-1-(2,4,6-trimethylbenzyl)-1H-indole-2-carboxylic acid

Step 1: 5-bromo-1-[(2,4,6-trimethylphenyl)methyl]indole-2-carboxylicacid (0.7000 g, 1.880 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (68.78 mg, 0.09400 mmol), aqueous sodium carbonate(1.880 mL of 2 M, 3.760 mmol), and2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (315.9 mg, 1.880mmol) in dioxane (5 mL) were added to a microwave reactor vial. The vialwas purged with nitrogen, capped and heated to 120° C. for 45 minutes ina microwave reactor. The reaction mixture was diluted with water andextracted with ethyl acetate (2×10 mL). The organic layers were driedover sodium sulfate, concentrated, and purified by reverse-phasechromatography utilizing a C18 column and a gradient of 30-90%acetonitrile in 5 mM aq HCl to give a mixture of products which couldnot be separated under these specific condition. This material wasdissolved in methanol (10 mL) and palladium on carbon (20.01 mg, 0.01880mmol) was added to the reaction mixture The mixture was stirred under anatmosphere of hydrogen for 4 hours. The mixture of crude products wasfiltered, through a pad of silica gel with 100 mL of 15% methanol indichloromethane and used for the next step without further manipulation.ESI-MS m/z talc. 335.19, found 336.5 (M+1)⁺; Retention time: 0.84minutes.

PREPARATION 78: (4R)-2,2,4-trimethylpyrrolidine Step 1: Methyl2,4-dimethyl-4-nitropentanoate

A 1-L three-necked flask was fitted with a dropping funnel, and athermometer. A solution of 2-nitropropane (178 g, 2.00 mol) in dioxane(100 mL) and a 40% aqueous solution of benzyltrimethylammonium hydroxide(Triton B, 20.0 mL, 420. mmol) were added to the flask. The flask washeated to 70° C. in an oil bath and methyl methacrylate (200. g, 212.3mL, 2.00 mol) was added via a dropping funnel over 45 minutes. Thetemperature rose to about 100° C. during the addition then dropped to˜90° C. The mixture was then heated at 100° C. for 4 hours. The reactionmixture was cooled to room temperature and 1 N hydrochloric acid (80 mL)was added. Water (500 mL) and diethyl ether (1000 mL) were added to thereaction flask. The mixture was poured into a separatory funnel andorganic layer was washed with water (2×400 mL), brine (400 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a yellow liquid. The product was distilled through ashort path distillation apparatus to give a pale yellow liquid (356 g,94%) (oil bath temperature 150° C., an oil pump, collecting temperature100 to 108° C.). ¹H NMR (CDCl₃, 250 MHz): 3.67 (s, 3H), 2.55-2.35 (m,2H), 2.10-1.90 (m, 1H), 1.58 (s, 3H), 1.53 (s, 3H), 1.18 (d, J=6.5 Hz,3H).

Step (R)-3,5,5-trimethylpyrrolidin-2-one and(S)-3,5,5-trimethylpyrrolidin-2-one

A solution of methyl 2,4-dimethyl-4-nitro-pentanoate (100. g, 528.5mmol), nickel(II) chloride hexahydrate (25.12 g, 105.7 mmol), water(28.57 g, 28.57 mL, 1.586 mol) and methanol (1.200 L) was cooled to 0 to5° C. Sodium borohydride (49.98 g, 1.321 mol) was slowly added to thereaction mixture while maintaining the reaction temperature below 20° C.The addition was exothermic with steady and prolonged gas generation.THe reaction mixture was allowed to stand for 14 days. A solution ofpotassium carbonate (146.1 g, 1.057 mol) in water (1.000 L) was slowlyadded to the reaction mixture. The reaction mixture was then filteredthrough a pad of celite. The pad was then washed with three 100 mLportions of methanol. The reaction mixture was then concentrated underreduced pressure to remove the methanol. Methyl tert-butyl ether (1 L)was added. The layers were separated and the aqueous layer was extractedtwice with 400 mL portions of methyl tert-butyl ether. The combinedorganic layers were dried over sodium sulfate, filtered, and evaporatedto dryness. This material was then portioned between methyl tert-butylether and an aqueous solution of sodium chloride. The organic layer wasseparated, dried over magnesium sulfate, filtered, and then evaporatedto dryness to yield 41.5 g (61.7%) of an off-white solid. Thestereoisomers were separated using supercritical fluid chromatography ona ChiralPak AS-H (250×4.6 mm), 5 p.m column using 10% methanol in CO₂ ata flow rate of 3.0 mL/min.

Step 3: (4R)-2,2,4-trimethylpyrrolidine

A solution of (3R)-3,5,5-trimethylpyrrolidin-2-one (20.0 g, 157 mmol) intetrahydrofuran (200.0 mL) was cooled to 0 to 5° C. Lithium aluminumhydride (8.006 g, 236.0 mmol) was added in portions over 10 minuteswhile maintain the temperature of the reaction mixture below 20° C. Theaddition was somewhat exothermic and degassing was observed. Thesuspension was heated to reflux for 9.5 hours. After cooling to roomtemperature an additional portion of lithium aluminum hydride (1.601 g,1.746 mL, 47.19 mmol) was added to the reaction mixture. The mixture wasthen heated to reflux for 2.5 hours. The reaction mixture was cooled to7° C. and an aqueous solution of sodium sulfate (27.93 mL of 20% w/v,39.32 mmol) was slowly added to the reaction mixture. The reactionmixture was then diluted with 200 mL of methyl tert-butyl ether andfiltered through a pad of celite. The filtrate was dried over sodiumsulfate, filtered, and concentrated at ambient pressure to remove theethers. The crude material was purified by distillation (28° C./50 torr)to afford 10. g (56%) of a colorless liquid. 1H NMR (400 MHz,Chloroform-d) δ 3.11 (dd, J=10.8, 7.3 Hz, 1H), 2.51 (dd, J=10.9, 8.1 Hz,1H), 2.32-2.15 (m, 1H), 1.80 (dd, J=12.4, 8.1 Hz, 1H), 1.65 (s, 1H),1.19 (s, 3H), 1.17-1.08 (m, 4H), 1.01 (d, J=6.8 Hz, 3H). The absolutestereochemistry was determined by X-ray crystallography of the(2R)-2-(2-chlorophenyl)-2-hydroxy-acetic acid salt.

The following compounds can be synthesized using the proceduresdescribed herein

-   (S)-4-ethyl-2,2-dimethylpyrrolidine, and-   (R)-4-ethyl-2,2-dimethylpyrrolidine

The following compounds can be synthesized using the proceduresdescribed herein using lithium aluminum dueterohydride:

(S)-2,2,4-trimethylpyrrolidine-5,5-d₂ and,

-   (R)-2,2,4-trimethylpyrrolidine-5,5-d₂

Preparation 79: 3-Isobutoxy-1H-pyrazole Step 1:1-(3-isobutoxy-1H-pyrazol-1-yl)ethan-1-one

A 4 mL vial was charged with 1-(3-hydroxypyrazol-1-yl)ethanone (100. mg,0.793 mmol), potassium carbonate (164.3 mg, 1.189 mmol) and anhydrousDMF (1.000 mL). 1-bromo-2-methyl-propane (119.5 mg, 94.84 μL, 0.8722mmol) was added, the vial was capped and the mixture was stirred at roomtemperature for 16 hours. The reaction was stirred at 80° C. for onehour. The mixture was diluted with ethyl acetate (50 ml) and water (25mL) and the two phases were separated. The aqueous phase (pH=9-10) wasfurther extracted with ethyl acetate (20 mL). The combined extracts weredried over sodium sulfate and the solvents evaporated to give 100 mg ofa crude oil. The product was dissolved in dichloromethane and purifiedby flash chromatography on silica gel (4 g column) using a gradient ofethyl acetate (0 to 50% over 15 minutes) in hexanes. The pure fractionswere combined and the solvents removed under reduced pressure to provide1-(3-isobutoxypyrazol-1-yl)ethanone (78 mg, 0.43 mmol, 54%) as acolorless oil.

ESI-MS m/z calc. 182.10553, found 183.2 (M+1)⁺; Retention time: 1.34minutes. ¹H NMR (400 MHz, Chloroform-d) δ 8.05 (d, J=3.0 Hz, 1H), 5.96(d, J=3.0 Hz, 1H), 3.99 (d, J=6.6 Hz, 2H), 2.58 (s, 3H), 2.09 (dp,J=13.4, 6.7 Hz, 1H), 1.01 (d, J=6.7 Hz, 6H).

Step 2: 3-lsobutoxy-1H-pyrazole

1-(3-Isobutoxy-1H-pyrazol-1-ypethan-1-one (72 mg, 0.40 mmol) was treatedwith methanol (1 mL) and NaOH (65.85 μL of 6 M, 0.3951 mmol) at roomtemperature for 1 hour. The volatiles were removed under reducedpressure. The residue was taken up in ethyl acetate (25 mL) and brine(20 mL)and two phases were separated. The aqueous phase was furtherextracted with ethyl acetate (20 mL) and the combined extracts weredried over sodium sulfate. After evaporation of the solvent,3-isobutoxy-1H-pyrazole (55 mg, 0.39 mmol, 99%) was isolated as acolorless viscous oil. ESI-MS m/z calc. 140.09496, found 141.2 (M+1)⁺;Retention time: 0.86 minutes. ¹H NMR (400 MHz, Chloroform-d) 7.34 (d,J=2.4 Hz, 1H), 5.71 (d, J=2.5 Hz, 1H), 3.90 (d, J=6.6 Hz, 2H), 2.08 (dq,J=13.3, 6.7 Hz, 1H), 1.00 (d, J=6.7 Hz, 6H).

The following compounds can be synthesized using the proceduresdescribed herein

-   3-isobutoxy-5-methyl-1H-pyrazole,-   4-isobutoxy-1H-pyrazole, and-   3-isobutoxy-4-methyl-1H-pyrazole

Preparation 80:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-earboxamide(Compound 1620) Step 1: tert-Butyl2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylate

A 4 mL vial was charged under nitrogen with with 3-isobutoxy-1H-pyrazole(131.5 mg, 0.9383 mmol) and anhydrous DMF (1 mL), Sodium hydride (37.48mg, 0.9370 mmol, 60% in mineral oil) was added and the mixture wasstirred until gas evolution stopped. tert-Butyl2,6-dichloropyridine-3-carboxylate (155 mg, 0.625 mmol) was added. Thevial was capped and the mixture was stirred at 100° C. for 4 hours. LCMSshowed the presence of two mono addition isomers (ratio approx. 60:40)and a major product being a double addition product. The reactionmixture was diluted with ethyl acetate (30 mL) and water (20 mL) and thetwo phases were separated. The aqueous phase was further extracted withethyl acetate (25 mL). The combined extracts were dried over sodiumsulfate and the solvent removed under reduced pressure to give 247 mg ofcrude solid. The residue was dissolved in dichloromethane and subjectedto flash chromatography on silica gel (40 g column) using a gradient ofethyl acetate (0 to 20% over 20 minutes) in hexanes to yield tert-butyl2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylate (58 mg,0.1649 mmol, 26.39%) (off-white solid). ESI-MS m/z talc. 351.13498,found 352.4 (M+1)⁺; Retention time: 2.25 minutes.

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxamide

A 100 mL round bottom flask containing tert-butyl2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylate (58 mg, 0.16mmol) was treated with dichloromethane (600 μL) and trifluoracetic acid(180 μL, 2.336 mmol). The mixture was stirred at 45° C. for 1.5 hours.The volatiles were removed under reduced pressure to give a white solid.Anhydrous DMF (500 μL) was then added to the 100 mL flask containing theacid under an atmosphere of nitrogen and the mixture was stirred at 40°C. 1,1′-Carbonyldiimidazole (32.09 mg, 0.1979 mmol) was added and themixture was stirred at 40° C. for 1 hour. A separate 4 mL vial undernitrogen was charged with 6-aminopyridine-2-sulfonamide (34.27 mg,0.1979 mmol) and anhydrous DMF (500 μL). NaH (7.915 mg, 0.1979 mmol, 60%oil dispersion) was added. After gas evolution had stopped, the vial wascapped and it was stirred at 40° C. for 1 hour. This mixture was addedto the first flask and the mixture was stirred at room temperature for 2hours. The reaction was quenched with ice and water an neutralized withacetic acid (148.6 mg, 140.7 μL, 2.474 mmol, final pH=4). The resultingwhite solid was filtered, washed with water and dried under reducedpressure.N-[(6-amino-2-pyridyl)sulfonyl[-2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxamide(57 mg, 0.13 mmol, 77%) was isolated as a white solid. ESI-MS m/z calc.450.0877, found 451.3 (M+1)⁺; Retention time: 1.54 minutes

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1620)

A 4 mL vial was charged under nitrogen withN-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxamide(57 mg, 0.13 mmol), CsF (96.00 mg, 0.6320 mmol), potassium carbonate(87.35 mg, 0.6320 mmol), (4S)-2,2,4-trimethylpyrrolidine (47.64 mg,0.3792 mmol) and anhydrous dimethylsulfoxide (200 μL). The vial wascapped and the contents were stirred at 150° C. for 4 hours. The mixturewas diluted with water (200 uL), N-methylpyrrolidinone (600 uL) and themixture was filtered. The compound was purified by reverse phasepreparative HPLC using a gradient of acetonitrile in water (1 to 99%over 15 minutes) in 5 mM aqueous ammonium formate. The pure fractionswere combined, a few drops of brine was added and the organic solventswere removed under reduced pressure. The solid that crashed out wasextracted with dichloromethane (3×20 mL). The combined extracts weredried over sodium sulfate, filtered, and the solvents were removed underreduced pressure to give 28 mg of material that still contained animpurity. The material was purified a second time by preparative HPLCusing a gradient of acetonitrile in water (1 to 99% over 15 minutes) in5 mM aqueous hydrochloric acid. The product was isolated using the sameextraction procedure. After concentration of the dichloromethane, asolid was obtained by adding hexanes. Evaporation of the solvents gaveN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1620) (18 mg, 0.03394 mmol, 26.86%) as an off-white solid.ESI-MS m/z calc. 527.23145, found 528.5 (M+1)⁺; Retention time: 1.77minutes. ¹H NMR (400 MHz, Chloroform-d) 13.87 (broad s, 1H), 8.29 (d,J=8.0 Hz, 1H) 8.21 (d, J=2.9 Hz, 1H), 7.65-7.58 (m, 2H), 7.52 (d, J=8.5Hz, 1H), 6.65 (p, J=3.8 Hz, 1H), 5.95 (d, J=2.8 Hz, 1H), 4.80 (broad s,2H), 4.02 (d, J=6.6 Hz, 2H), 3.52-3.41 (m, 1H), 3.15 (dd, J=10.5, 8.1Hz, 1H), 2.69-2.50 (m, 1H), 2.18-2.02 (m, 2H), 1.72 (dd, J=12.3, 9.7 Hz,1H), 1.45 (s, 3H), 1.39 (s, 3H), 1.19 (d, J=6.6 Hz, 3H), 1.02 (d, J=6.7Hz, 6H).

The following compounds can be synthesized using the proceduresdescribed herein

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxy-5-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1407),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(cyclobutylmethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl[pyridine-3-carboxamide    (Compound 2694),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(cyclopropylmethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2695),-   N-[(2-amino-3-pyridyl)sulfonyl]-643-(2,2-dimethylpropoxy)-4-methyl-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2699),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1411),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(5-isobutylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1431),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1443),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1473), and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxy-4-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1532)

Preparation 81:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(3,4-dihydro-2H-pyran-5-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 1487) Step 1:5-bromo-6-tert-butyl-2-hydroxypyridine-3-carbonitrile

N-Bromosuccinimide (10.3 g, 57.9 mmol) was added to6-tert-butyl-2-hydroxypyridine-3-carbonitrile (6.8 g, 38.6 mmol) in1,2-dichloroethane (50 mL) and the reaction mixture was refluxed for 3h. Water was added and extracted twice with dichloromethane (2×50 mL).The organic phase was washed with water, dried with anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography (100% dichloromethane to 10%methanol/90% dichloromethane) to provide5-bromo-6-tert-butyl-2-hydroxypyridine-3-carbonitrile in 65% yield (6.4g) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) ppm 1.43 (s, 9H), 8.36(s, 1H). [M+H⁺=255.0, 257.0.

Step 2: 5-bromo-6-tert-butyl-2-chloropyridine-3-carbonitrile

Phosphorus oxychloride (30.3 mL, 325 mmol) and phosphorus pentachloride(20.3 g, 97.6 mmol) were added to5-bromo-6-tert-butyl-2-hydroxypyridine-3-carbonitrile (8.30 g, 32.5mmol) and the reaction mixture was refluxed for 2 days. The reactionmixture was cooled to room temperature and concentrated under reducedpressure. Water was added to the residue, extracted 3 times with ethylacetate (75-mL portions), washed with brine (75 mL), dried withanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography (100%heptanes to 50% ethyl acetate/50% heptanes) to provide5-bromo-6-tert-butyl-2-chloroxypyridine-3-carbonitrile in 39% yield (3.5g) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) ppm 1.52 (s, 9H), 8.08(s, 1H). [M+H]⁺=273.0, 275.0.

Step 3: 5-bromo-6-tert-butyl-2-chloropyridine-3-carboxylic acid

Potassium hydroxyde (4.3 g, 77 mmol) in water (15 mL) was added to5-bromo-6-tert-butyl-2-chloroxypyridine-3-carbonitrile in 2-propanol (15mL) and the reaction mixture was heated at 90° C. for 16 hours. Ethylacetate (50 mL) was added and extracted 3 times with 1N sodium hydroxide(3×50 mL). The aqueous phase was acidified to pH ˜4 with 10%hydrochloric acid and the aqueous phase was extracted 3 times with ethylacetate (3×75 mL), and washed with brine (100 mL). The desired compoundwas present in all organic phases so they were combined, dried withanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude compound was purified by reverse phasechromatography (methanol/water, 0 to 100%) to afford5-bromo-6-tert-butyl-2-chloropyridine-3-carboxylic acid (2.3 g, 61%yield) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) ppm 1.53 (s, 9H),8.46 (s, 1H). [M+H]⁺=292.0, 294.0.

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-6-tert-butyl-2-chloro-pyridine-3-carboxamide

To a stirred solution of5-bromo-6-tert-butyl-2-chloro-pyridine-3-carboxylic acid (500.0 mg,1.709 mmol) in dry DMF (3.5 mL) in a 50 mL round-bottom flask was added1,1′-carbonyldiimidazole (346.3 mg, 2.136 mmol) in one portion undernitrogen at ambient temperature. The reaction was warmed to 45° C. andstirred for 1.5 h. In a separate 50 mL round-bottom flask,6-aminopyridine-2-sulfonamide (369.9 mg, 2.136 mmol) was dissolved indry DMF (2.5 mL) under nitrogen and sodium hydride (60% in mineral oil)(85.43 mg, 2.136 mmol) was added in portions to mitigate gas evolutionat ambient temerature. The heterogeneous mixture was warmed to 40° C.and stirred for 1 hour. This mixture was added to the stirred activatedacid mixture in one portion at 45° C. Heating was stopped and thereaction was stirred for an additional hour. The reaction mixture fromwas slowly (over 2 minutes) added to ice-cold water (50 mL) in a 100 mLround-bottom flask, and placed in an ice bath. Then acetic acid (528.5mg, 500.5 μL, 8.801 mmol) was added and the mixture stirred vigorouslyfor 10 minutes and the solids were filtered and washed with water (3×20mL). The solids were slurried in hexanes (20 mL) and filtered. The solidwas further and dried to furnish desired coupled product as white solid.N4(6-amino-2-pyridyl)sulfonyl]-5-bromo-6-tert-butyl-2-chloro-pyridine-3-carboxamide(585 mg, 1.31 mmol, 76.5%)'H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.15(s, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.3Hz, 1H), 6.58 (d, 8.3 Hz, 1H), 6.35 (s, 2H), 1.46 (s, 9H) ESI-MS m/zcalc. 445.9815, found 449.2 (M+1)⁺; Retention time: 1.52 minutes

Step 5:N-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 1628)

2,2,4-Trimethylpyrrolidine (252.9 mg, 2.234 mmol) and potassiumcarbonate (617.5 mg, 4.468 mmol) were added to a solution ofN[(6-amino-2-pyridyl)sulfonyl]-5-bromo-6-tert-butyl-2-chloro-pyridine-3-carboxamide(500.0 mg, 1.117 mmol) in anhydrous DMSO (4.0 mL) in a 20 mL reactionvial. The vial was capped under a nitrogen atmosphere and heated in apre-heated oil bath at 145° C. for 24 h. The reaction vessel was removedand allowed to cool to ambient temerature. The reaction mixture waspoured onto a mixture of ice and water (50 mL) with stirring. Theresulting reaction mixture was then adjusted to a pH of about 6.0 with 1M aqueous HCl. The mixture was vigorously stirred for 15 minutes. Thesoild was filtered, washed with water (4×20 mL), and dried under vacuumto yield the desired product as white soild.

-   N-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1628) (495 mg, 0.944 mmol, 84.5%) ¹H NMR (400 MHz,    DMSO-d₆) δ 12.49 (s, 1H), 8.52 (s, 1H), 7.70 (s, 1H), 7.49 (s, 1H),    7.07 (d, J=7.2 Hz, 1H), 6.53 (s, 1H), 6.20 (s, 2H), 3.37 (dd,    J=11.6, 8.2 Hz, 1H), 2.77 (dd, J=11.6, 8.9 Hz, 1H), 2.16 (dt,    J=12.5, 6.4 Hz, 1H), 1.99 (dd, J=12.9, 7.6 Hz, 1H), 1.81 (dd,    J=11.8, 5.5 Hz, 1H), 1.51 (s, 3H), 1.48 (s, 3H), 1.44 (s, 9H), 0.87    (d, J=6.3 Hz, 3H). ESI-MS m/z calc. 523.12524, found 526.1 (M+1)⁺;    Retention time: 1.43 minutes

Step 6:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(3,4-dihydro-2H-pyran-5-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 1487)

A 4 mL vial was charged with a stir bar,N-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 1628) (29 mg, 0.055 mmol) and vinylboronic acid 34.85 mg,0.1659 mmol). Then DMF (0.5 mL) and water (0.1 mL) were added, followedby potassium carbonate (30.57 mg, 0.2212 mmol). Nitrogen was bubbledthrough the vial for 1 min. Then tetrakis(triphenylphosphine)palladium(0) (6.389 mg, 0.005529 mmol) was added and nitrogen was bubbled throughthe solution for another 1 min, sealed with a screw cap under nitrogenand heated at 130° C. (external temperature) for 13 h. The reactionmixture was filtered through a syringe filter disc, and purified byreverse phase HPLC utilizing a gradient of 10 to 99 percent acetonitrilein water containing 5 mM HCl to yieldN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(3,4-dihydro-2H-pyran-5-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 1487) (3.3 mg, 0.0058 mmol, 11%) as the hydrochloric acidsalt. ESI-MS m/z calc. 527.26, found 528.3 (M+1)⁺; Retention time: 1.21minutes

The following compounds can be synthesized using the proceduresdescribed herein

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[4-(trifluoromethyl)cyclohexen-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1380),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-3,3-dimethylbut-1-enyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1613),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclohexylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1484),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-hex-1-enyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1377),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-5-methylhex-1-enyl]-2-[(4S)-2,2,4-trimethylpynolidin-1-yl]pyridine-3-carboxamide    (Compound 1682),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclopentylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1633),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1566),

(E)-3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-3-pyridyl]prop-2-enoicacid (Compound 1547),

-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-bicyclo[2.2.1]hept-2-enyl)-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-phenyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1364),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-phenyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1384),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4,7,7-trimethyl-3-bicyclo[2.2.1]hept-2-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1544),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-2-cyclopropylvinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1571),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(1,2-dimethylprop-1-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1590),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-(4-methoxyphenyl)vinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-pent-1-enyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-bicyclo[2.2.1]hept-2-enyl)-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   ethyl    (E)-3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]prop-2-enoate,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-ethoxyvinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)-5-vinyl-pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclopropylvinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-pent-1-enyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-(4-methoxyphenyl)vinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclopropylvinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)-5-vinyl-pyridine-3-carboxamide,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-ethoxyvinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide,-   ethyl    (E)-3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]prop-2-enoate,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-methylprop-1-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1561),-   benzyl    4-[51(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate    (Compound 1404),-   tert-butyl    345-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate    (Compound 1388),-   5-(4-acetylcyclohexen-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1461),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1,4-dioxaspiro[4.5]dec-8-en-8-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1459),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1628),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2,2,6,6-tetramethyl-3H-pyran-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1647),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(4,7,7-trimethyl-3-bicyclo[2.2.1]hept-2-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1578),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(3,4-dihydro-2H-pyran-6-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1485),-   N-[(6-ainino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(5,5-dimethyl-3-oxo-cyclohexen-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1405),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1,4-dioxaspiro[4.5]dec-8-en-9-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1469),-   tert-butyl    4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate    (Compound 1522),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1382),-   4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]cyclohex-3-ene-1-carboxylic    acid (Compound 1381),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-cyano-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1419),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1495),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-methoxy-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2499),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-hex-1-enyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1916),-   N4(6-amino-2-pyridyl)sulfonyl]-5-(3-isobutoxy-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2558),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1921),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-chlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2429),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-cyanophenyl)-2-(2,2,4-trimethylpyrroliclin-1-yl)pyridine-3-carboxamide    (Compound 1849),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-methoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1792),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-tert-butyl-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2322),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2112),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-tert-butylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2463),-   ethyl    3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-4-methoxy-benzoate    (Compound 2134),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-chlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2399),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-chloro-5-methoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2545),-   N4(6-amino-2-pyridyl)sulfonyl]-5-(2-methoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1735),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-cyanophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2304),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-isopropylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1809),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-isopropoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2283),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[3-(2-methoxyethoxymethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1943),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2089),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-isobutylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2395),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(1H-indazol-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2157),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(1-hydroxy-1-methyl-ethyl)phenyl    ]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide (Compound    2547),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2014),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[3-(cyclopentoxy)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1918),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(6-ethoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2384),-   N-[(6-amino-2-pyridyl)sulfonyl]-(o-tolyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1701),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(1-cyano-1-methyl-ethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2521),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(6-methoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1886),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[3-(cyclopentoxy)-5-methyl-phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2313),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-dimethylaminophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2288),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(1-isobutylpyrazol-3-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2303),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-methoxycyclohexen-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1920),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-cyanophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2584),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-chloro-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1963),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(trifluoromethoxy)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2649),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-ethoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2557),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3,5-dimethylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2093),-   tert-butyl    4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate    (Compound 2129),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(4-methylcyclohexen-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2361),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isopentyloxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1894),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[3-(trifluoromethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1950),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-5-methylhex-1-enyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2647),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(6-methoxy-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1861),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[3-isopropoxy-5-(trifluoromethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1815),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-methoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2431),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(1,1,4,4,7-pentamethyltetralin-6-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1759),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isopropoxy-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1889),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3,5-dichlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1721),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1979),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(5-benzyloxy-2-methyl-phenyl)-2-(2,2,4-trimethylpyrroliclin-1-yl)pyridine-3-carboxamide    (Compound 2588),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isopropoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1804),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3,5-difluorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2259),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(hydroxymethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2088),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(trifluoromethyl)cyclohexen-1-yl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2510),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(m-tolyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2184),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-chlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2312),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(trifluoromethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2337),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(2-chloro-5-isopropoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2210),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-methoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2031),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-tert-butylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2180),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-2-(4-methoxyphenyl)vinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1726),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-bicyclo[2.2.1]hept-2-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1888),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-ethoxy-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1843),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-methyl-4-propoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2095),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-2-cyclohexylvinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2063),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(cyclohexen-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1601), and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1-methylpyrazol-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1441)

Preparation 82: tert-butylN-[14[6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-3-methyl-3-piperidyl]carbamate(Compound 1520)

A solution of6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxylicacid (40.45 mg, 0.1000 mmol) and chlorosulfonyl isocyanate (16.98 mg,10.44 4, 0.1200 mmol) in dichloromethane (1.000 mL) was stirred for 45minutes. Triethylamine (15.18 mg, 20.91 μL, 0.1500 mmol) andtert-butyl-N-(3-methyl-3-piperidyl)carbamate (32.15 mg, 0.1500 mmol)were added, and the reaction was stirred for three days. The reactionwas purified by silica gel chromatography with 0-5% methanol indichloromethane to give tert-butyl(1-(N-(6-(3-fluoro-5-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinoyl)sulfamoyl)-3-methylpiperidin-3-yl)carbamate(34 mg, 0.050 mmol, 50.%) as a colorless solid.

The following compounds can be synthesized using the proceduresdescribed herein

-   N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1360),-   N-(3-acetamidopyrrolidin-1-yl)sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1391),-   N-[[3-(dimethylamino)-1-piperidyl]sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1414),-   N-[[(3S)-3-amino-1-piperidyl]sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1435),-   N-[(3-amino-3-methyl-1-piperidyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1445),-   N-[(3-amino-1-piperidyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1447)-   N-(3-aminopyrrolidin-1-yl)sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1467),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[3-(methylamino)-1-piperidyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1508),-   N-[(5-amino-3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1521),-   N-((3-[acetyl(methyl)amino]pyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1533),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(3-methoxy-1-piperidyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1545),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-((3-(methylamino)pyrrolidin-1-yl]sulfonyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1554),-   N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1557),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-methylsulfonylpyrrolidin-1-yl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1560),-   N-[(3-acetamido-1-piperidyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1586),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[3-(methanesulfonamido)-1-piperidyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1600),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(3-hydroxy-1-piperidyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1608),-   N-[[(3R)-3-amino-1-piperidyl]sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1614),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-pyrrolidin-1-ylsulfonyl-2-[(4S)-2,2,4-trimethylpyrroliclin-1-yl]pyridine-3-carboxamide    (Compound 1619), and-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-hydroxypyrrolidin-1-yl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1648),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-hydroxy-3-methyl-azetidin-1-yl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2398),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(2-pyridylsulfamoyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[(4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1789),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[(3R)-3-piperidyl]sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2677),-   N-[(6-amino-2-pyridyl)sulfamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-pyridylsulfamoyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1448),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-methoxy-3-pyridyl)sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1359),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2347),-   N-(3,3-difluoropyrrolidin-1-yl)sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolichn-1-yl]pyridine-3-carboxamide    (Compound 1956),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   N-(3,8-diazabicyclo[3.2.1]octan-3-ylsulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2237),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(3R)-3-hydroxypyrrolidin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2427),-   N-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2534),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[(3S)-pyrrolidin-3-yl]sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1935),-   N-[(5-amino-3,3-difluoro-1-piperidyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2209),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-methoxy-2-pyridyl)sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[(3R)-pyrrolidin-3-yl]sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(3S)-3-fluoropyrrolidin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2228),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(3R)-3-methoxypyrrolidin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1893),-   N-[(3,3-difluoro-5-hydroxy-1-piperidyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2508),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[(3S)-3-piperidyl]sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,-   N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-2-(2-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2325) (Isomer 1, R or S stereoisomer)-   N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2477) (Isomer 2, R or S stereoisomer)

Preparation 83:1-[3-[fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-2-olStep 1: 1-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-2-ol

To 3-bromo-5-fluoro-phenol (9.0 g, 47 mmol), and1-chloro-2-methyl-propan-2-ol (5.116 g, 47.12 mmol), aqueous sodiumhydroxide (37.69 g, 94.24 mmol) was added and the reaction mixture washeated at 120° C. for 5 days in a pressure vessel. The reaction wascooled and then extracted three times with ethyl acetate. The combinedorganic layer was dried over sodium sulfate, filtered, and the solventwas evaporated under reduced pressure. The crude product was purified on220 g of silica gel utilizing a gradient of 0 to 10% ethyl acetate indichloromethane. The impure product was repurified on 220 g of goldsilica gel utilizing a gradient of 0 to 10% ethyl acetate indichloromethane to yield1-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-2-ol (4.75 g, 18.0 mmol,38%). ESI-MS m/z calc. 262.00046, found 263.0 (M+1)⁺; Retention time:1.57 minutes (3 min run).

Step 2:1-[3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-2-ol

To 1-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-2-ol (5.250 g, 19.95mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(7.598 g, 29.92 mmol) in a flask was added potassium acetate (4.894 g,49.87 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (729.9 mg, 0.9975 mmol) followed bydioxane (32.58 mL). The suspension was degassed for 10 minutes bysparging with nitrogen and then the reaction was heated in an oil bathat 85° C. for 3 h. The reaction was diluted with ethyl acetate,filtered, and concentrated. The crude product was purified on 330 g ofsilica gel utilizing a gradient of 0 to 50% ethyl acetate in hexane toyield1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-2-ol(5.23 g, 16.86 mmol, 84.52%). The product was not pure and it was usedin the next step without further purification. ESI-MS m/z calc.310.17517, found 311.5 (M+1)⁺; Retention time: 1.895 minutes (3 minrun).

Preparation 84:343-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-1-olStep 1: 3-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-1-ol

To a stirred solution of 3-bromo-5-fluoro-phenol (2.270 g, 11.88 mmol),2-methylpropane-1,3-diol (1.071 g, 11.88 mmol) and triphenylphosphane(3.428 g, 3.028 mL, 13.07 mmol) in tetrahydrofuran (71.82 mL) at 0° C.was added diisopropyl azodicarboxylate (2.643 g, 2.532 mL, 13.07 mmol).The ice bath was removed and the reaction was stirred at 55° C. for 18h. The reaction was diluted with ethylacetate and washed twice withsodium bicarbonate and twice with brine. The organic layer was driedover sodium sulfate, filtered and the solvent was evaporated underreduced pressure. The crude product was purified on 220 g of silica gelutilizing a gradient of 0 to 15% ethyl acetate in dichloromethane toyield 3-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-1-ol (1.73 g, 6.57mmol, 55.3%) as a colorless liquid. NMR (400 MHz, DMSO-d₆) δ 7.09-7.03(m, 1H), 7.03-6.98 (m, 1H), 6.87 (dt, J=11.2, 2.3 Hz, 1H), 4.57 (t,J=5.3 Hz, 1H), 3.97 (dd, J=9.5, 5.9 Hz, 1H), 3.85 (dd, J=9.5, 6.3 Hz,1H), 3.48-3.34 (m, 2H), 2.05-1.84 (m, 1H), 0.94 (d, J=6.8 Hz, 3H).ESI-MS m/z calc. 262.00046, found 265.0 (M+1)+; Retention time: 1.58minutes (3 min run).

Step 2:343-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-1-ol

To 3-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-1-ol (1.7 g, 6.5 mmol)and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2.461 g, 9.692 mmol) in a flask was potassium acetate (1.585 g, 16.15mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane adduct (236.3 mg, 0.3230 mmol) followed by dioxane(10.55 mL). The suspension was degassed for 10 min by bubbling nitrogenthrough the reaction mixture and then the reaction was heated in an oilbath at 85° C. for 2.5 h. The reaction was diluted with ethyl acetate,filtered, and concentrated. The crude product was purified on 220 g ofsilica gel utilizing a gradient of 0 to 50% ethyl acetate in hexane toyield3-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-1-ol(1.77 g, 5.71 mmol, 88%) as an orange viscous liquid. The productcontained some impurity. It was used in the next step without furtherpurification. ESI-MS m/z calc. 310.17517, found 311.2 (M+1)⁺; Retentiontime: 1.81 minutes (3 min run).

Preparation 85: 5-(Benzyloxy)-6-nitropyridine-2-sulfonamide Step 1:3-Benzyloxy-6-bromo-2-nitro-pyridine

To a solution of 6-bromo-2-nitro-pyridin-3-ol (1.36 g, 6.21 mmol) inN,N-dimethylformamide (15 mL) was added potassium carbonate (1.717 g,12.42 mmol) followed by the addition of bromomethylbenzene (1.115 g,775.4 μL, 6.520 mmol). The mixture was heated at 60° C. overnight, andpartitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate three times. The combined organic layerswere washed three times with water, brine, dried over magnesium sulfate,filtered, and concentrated to dryness. The crude material was suspendedin hexane, collected via filtration and air dried to provide3-benzyloxy-6-bromo-2-nitro-pyridine (1.61 g, 5.21 mmol, 83.8%) as ayellow solid. ¹H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J=8.7 Hz, 1H),7.45-7.29 (m, 6H), 5.25 (s, 2H).

Step 2: Methyl 3-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]propanoate

A mixture of 3-benzyloxy-6-bromo-2-nitro-pyridine (585 mg, 1.89 mmol)and (3-methoxy-3-oxo-propyl)sulfinyloxysodium (329.5 mg, 1.892 mmol) indimethylsulfoxide (5 mL) was purged with nitrogen for 2 minutes.Iodocopper (720.7 mg, 3.784 mmol) was added to the reaction mixture. Themixture was heated at 80° C. overnight, partitioned between ethylacetate and a saturated aqueous solution of ammonium chloride. Theresulting precipitate was removed by filtration and washed with ethylacetate. The aqueous layer was extracted three times with ethyl acetate.The combined organic layers were washed three times with water, brine,dried over magnesium sulfate, filtered and concentrated to dryness. Thecrude material was purified by column chromatography (40-60% ethylacetate in hexanes) to provide methyl3-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]propanoate (210. mg, 0.552mmol, 29.2%) as a pale yellow solid. ¹H NMR (400 MHz, Chloroform-d) δ8.20 (d, J=8.6 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.50-7.31 (m, 5H), 5.35(s, 2H), 3.75-3.63 (m, 5H), 2.87 (t, J=7.5 Hz, 2H).

Step 3: 5-(Benzyloxy)-6-nitropyridine-2-sulfonamide

Tetrahydrofuran (10 mL) was added to a suspension of methyl3-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]propanoate (1.141 g, 3.000mmol) in methanol (20 mL). The resulting solution was cooled to 0° C.Sodium methoxide (6.000 mL of 0.5 M in methanol, 3.000 mmol) was addedin a dropwise manner. The mixture was stirred at room temperature for 15minutes. The mixture was evaporated to dryness to provide a light brownsolid. This solid was then suspended in dichloromethane (30 mL) andN-chlorosuccinimide (400.6 mg, 3.000 mmol) was added to the reactionmixture. The mixture was stirred at room temperature for 10 minutes. Thereaction was recharged with N-chlorosuccinimide (80.12 mg, 0.6000 mmol).The mixture turned clear. The mixture was stirred at room temperaturefor 5 minutes. The resulting solution was added to ammonia (36 mL of 0.5M, 18.00 mmol) at 0° C. The mixture was stirred at room temperature for30 minutes, and then partitioned between dichloromethane and water. Theaqueous layer was extracted three times with dichloromethane. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated to dryness to provide a yellow solid(342 mg). The crude material was used directly in next step withoutfurther purification. ESI-MS m/z calc. 309.04, found 310.3 (M₊1)⁺;Retention time: 1.10 minutes (3 min run).

Preparation 86:N-[(6-amino-2-pyridyl)sulfonyl]-3-fluoro-4-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)benzamide(Compound 1497) Step 1:N-[(6-amino-2-pyridyl)sulfonyl]-4-bromo-2,3-difluoro-benzamide

To 4-bromo-2,3-difluoro-benzoic acid (2.66 g, 11.2 mmol) inN,N-dimethylformamide (2.3 mL) was added at room temperaturedi(imidazol-1-yl)methanone (2.7 g, 17 mmol) and reaction was heated at65° C. for 1 hour. Separately to 6-aminopyridine-2-sulfonamide (2.4 g,14.0 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (561mg, 14.0 mmol) at 0° C. and stirred for 10 minutes for 1 hour. Thereaction was cooled back to 0° C. and the adduct from above was addedand the reaction was heated at 65° C. for 1.5 hours. The reaction wascooled to room temperature and diluted with ethyl acetate and washedwith a brine solution. The organics were separated, dried andconcentrated to give a residue which was purified with silica geleluting with 0 to 100% ethyl acetate in hexanes to giveN-[(6-amino-2-pyridyl)sulfonyl]-4-bromo-2,3-difluoro-benzamide (3.8 g,9.7 mmol, 86%) as product. ESI-MS m/z calc 390.94, found 392.0 (M+1)⁺;Retention time: 1.1 minutes (3 min run)

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-2,3-difluoro-4-(3-fluoro-5-isobutoxy-phenyl)benzamide

To mixture ofN-[(6-amino-2-pyridyl)sulfonyl]-4-bromo-2,3-difluoro-benzamide (700. mg,1.79 mmol), (3-fluoro-5-isobutoxy-phenyl)boronic acid (568 mg, 2.68mmol), and potassium carbonate (740 mg, 5.4 mmol) in a vial was added[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (130.6mg, 0.1785 mmol) and N,N-dimethylformamide (4.8 mL) and water (1.2 mL)and the reaction mixture was stirred under nitrogen at 100° C. for 16hours. The reaction mixture was cooled, filtered over pad of celite andthe filtrate was diluted with ethyl acetate and a brine solution. Theorganics were separated, dried over sodium sulfate, and concentrated togive a residue which was purified with silica gel using 5 to 100% ethylacetate in dichloromethane to giveN-[(6-amino-2-pyridyl)sulfonyl]-2,3-difluoro-4-(3-fluoro-5-isobutoxy-phenyl)benzamide(174 mg, 0.363 mmol, 20.3%) ¹H NMR (400 MHz, Methanol-d₄) δ 7.64-7.53(m, 2H), 7.29 (d, J=7.4 Hz, 1H), 7.25-7.18 (m, 1H), 6.90 (d, J=2.7 Hz,1H), 6.88-6.81 (m, 1H), 6.73 (dt, J=10.8, 2.3 Hz, 1H), 6.64 (d, J=8.3Hz, 1H), 3.79 (d, J=6.4 Hz, 2H), 2.07 (hept, J=6.7 Hz, 1H), 1.04 (d,J=6.7 Hz, 6H). ESI-MS m/z calc 479.11, found 480.2 (M+1)⁺; LCMSretention time: 1.8 minutes (3 min run).

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-3-fluoro-4-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)benzamide(Compound 1497)

To mixture of 2,2,4-trimethylpyrrolidine (35.41 mg, 0.3128 mmol) andN-[(6-amino-2-pyridyl)sulfonyl]-2,3-difluoro-4-(3-fluoro-5-isobutoxy-phenyl)benzamide(30.00 mg, 0.06257 mmol) was added 1-methylpyrrolidin-2-one (0.3 mL) andthe reaction mixture was heated 190° C. for 2 hours. The reactionmixture was cooled and purified by reverse phase HPLC utilizing agradient of 10 to 99 percent acetonitrile in water containing 5 mMammonium formate to yieldN-[(6-amino-2-pyridyl)sulfonyl]-3-fluoro-4-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)benzamide(Compound 1497) (7.6 mg, 0.013 mmol, 4.2%) ¹H NMR (400 MHz, Methanol-d₄)a 8.03 (dd, J=8.3, 1.2 Hz, 1H), 7.68 (dd, J=8.5, 7.3 Hz, 1H), 7.59 (dd,J=8.3, 7.1 Hz, 1H), 7.38 (dd, J=7.4, 0.8 Hz, 1H), 6.93-6.82 (m, 2H),6.82-6.74 (m, 2H), 3.92 (t, J=9.4 Hz, 1H), 3.79 (d, J=6.4 Hz, 2H),2.84-2.72 (m, 1H), 2.23 (dd, J=12.6, 7.3 Hz, 1H), 2.12-2.02 (m, 1H),1.87 (t, J=11.7 Hz, 1H), 1.38 (s, 3H), 1.24 (d, J=6.6 Hz, 6H), 1.04 (d,J=6.7 Hz, 6H). ESI-MS m/z calc. 572.23, found 573.1 (M+1)⁺; LCMSretention time: 1.77 minutes (3 min run).

Preparation 87:N-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1641)

N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(56.79 mg, 0.1022 mmol) and N-chlorosuccinimide (13.65 mg, 0.1022 mmol)in dichloromethane (400 μL) was stirred at reflux overnight. Thedichloromethane was evaporated under a stream of nitrogen, and theresidue was dissolved in dimethyl sulfoxide and purified by preparativeHPLC chromatography utilizing a gradient of 10 to 99 percentacetonitrile in water to giveN-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1641) (18 mg, 0.030 mmol, 29.5%) NMR (400 MHz, DMSO-d₆) 12.59(s, 1H), 7.80 (s, 1H), 7.64 (dd, J=8.4, 7.3 Hz, 1H), 7.27-7.18 (m, 1H),7.10-6.99 (m, 2H), 6.93 (dt, J=11.0, 2.3 Hz, 1H), 6.70 (dd, J=8.4, 0.8Hz, 1H), 6.54 (s, 2H), 3.80 (d, J=6.6 Hz, 2H), 2.65-2.53 (m, 2H), 2.22(dt, J=11.5, 5.9 Hz, 1H), 2.08-1.96 (m, 1H), 1.84 (dd, J=12.0, 5.6 Hz,1H), 1.57-1.33 (m, 7H), 0.97 (d, J=6.7 Hz, 6H), 0.86 (d, J=6.3 Hz, 3H).ESI-MS m/z calc. 589.19257, found 590.0 (M+1)⁺; Retention time: 3.06minutes.

Preparation 88:N-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1603)

N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 946) (40.0 mg, 0.102 mmol) and N-chlorosuccinimide (13.65 mg,0.1022 mmol) in dichloromethane (400 μL) was stirred at reflux for 3days. The reaction mixture was directly purified by chromatography oversilica gel (4 g) with a linear gradient of 0 to 5% methanol indichloromethane to giveN-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1603) (25 mg, 0.058 mmol, 57%) ¹H NMR (400 MHz, DMSO-d₆) 12.54(s, 1H), 8.27-8.00 (m, 1H), 7.72-7.54 (m, 2H), 7.18 (d, J=7.2 Hz, 1H),6.66 (d, J=8.4 Hz, 1H), 6.50 (s, 2H), 2.55 (s, 2H), 2.17 (dq, J=13.0,7.1, 6.7 Hz, 1H), 1.83 (dd, J=11.8, 5.6 Hz, 1H), 1.47 (d, J=7.1 Hz, 6H),1.37 (t, J=12.1 Hz, 1H), 0.85 (d, J=6.3 Hz, 3H). ESI-MS m/z calc.423.1132, found 424.0 (M+1)⁺; Retention time: 1.75 minutes.

Preparation 89:N-[(6-acetamido-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1652)

N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(56.78 mg, 0.1022 mmol) in pyridine (161.7 mg, 165.3 μL, 2.044 mmol) wastreated with acetic anhydride (104.3 mg, 96.40 μL, 1.022 mmol) andheated to 45° C. for 2.5 hours. The reaction mixture was diluted with a9:1 (v/v) mixture of dimethyl sulfoxide in water and purified bypreparative HPLC chromatography to giveN-[(6-acetamido-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1652) (22 mg, 0.036 mmol, 35%)

¹H NMR (400 MHz, DMSO-d₆) 12.68 (s, 1H), 10.87 (s, 1H), 8.35 (d, J=8.4Hz, 1H), 8.17-8.05 (m, 1H), 7.88-7.80 (m, 2H), 7.51-7.45 (m, 1H), 7.42(ddd, J=10.2, 2.4, 1.3 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.90 (dt,J=10.7, 2.3 Hz, 1H), 3.83 (d, J=6.6 Hz, 2H), 2.60 (dd, J=10.2, 7.2 Hz,1H), 2.52 (d, J=5.3 Hz, 1H), 2.14 (s, 4H), 2.07-2.00 (m, 1H), 1.87 (dd,J=11.8, 5.6 Hz, 1H), 1.59 (d, J=6.0 Hz, 6H), 1.41 (t, J=12.1 Hz, 1H),0.99 (d, J=6.7 Hz, 6H), 0.77 (d, J=6.3 Hz, 3H). ESI-MS m/z calc.597.2421, found 598.0 (M+1)⁺; Retention time: 2.83 minutes.

Preparation 90:N-((6-aminopyridin-2-yl)sulfonyl)-6-chloro-2-(3-fluoro-5-isobutoxyphenyl)nicotinamide

A mixture of N-((6-aminopyridin-2-yl)sulfonyl)-2,6-dichloronicotinamide(2.6 g, 7.4 mmol) and2-(3-fluoro-5-isobutoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.3 g, 7.7 mmol) in 12 mL of N,N-dimethylformamide and 3 mL of waterwas heated under nitrogen to 70° C. for 30 minutes and thentetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and sodiumcarbonate (4.8 g, 45 mmol) were added to the reaction mixture. Themixture was stirred at 70° C. for 18 hours and then purified by silicagel chromatography eluting with a gradient of 40 to 100% ethyl acetatein hexanes. The product was further purified on reverse phase HPLC and awhite solid was isolated asN-((6-aminopyridin-2-yl)sulfonyl)-6-chloro-2-(3-fluoro-5-isobutoxyphenyl)nicotinamide(0.37 g, 0.77 mmol, 14%). ¹H NMR (DMSO-d₆, 250 MHz): δ 8.03 (d, J=8.3Hz, 1H); 7.62 (m, 2H), 7.11 (d, J=7.3 Hz, 1H), 6.93 (m, 2H), 6.81 (d,J=9.3 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 3.87 (d, J=6.5 Hz, 2H), 2.02 (m,1H), 1.00 (d, J=6.5 Hz, 6H) ppm. LC-MS: (M+H)⁺=479.1

Preparation 91:N-((6-aminopyridin-2-yl)sulfonyl)-6-chloro-6’-isopropoxy-[2,3′-bipyridine]-3-carboxamide

A mixture of the sulfonamideN-((6-aminopyridin-2-yl)sulfonyl)-2,6-dichloronicotinamide (2.1 g, 6.0mmol) and2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.7 g, 6.6 mmol) in 12 mL of N,N-dimethylformamide and 3 mL of waterwas heated under nitrogen at 70° C. for 20 minutes and addedtetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mmol) and sodiumcarbonate (1.9 g, 18 mmol). The mixture was stirred at 70° C. for 19hours. The reaction mixture was evaporated to dryness, and the crudeproduct was purified by silica gel chromatography utilizing a gradientof 40 to 100% ethyl acetate in hexanes. The product was further purifiedon reverse phase HPLC and a white solid was isolated asN-((6-aminopyridin-2-yl)sulfonyl)-6-chloro-6′-isopropoxy-[2,3′-bipyridine]-3-carboxamide(0.72 g, 1.6 mmol, 27%). ¹H NMR (DMSO-d₆, 250 MHz): δ 8.33 (s, 1H), 8.06(d, J=8.0 Hz, 1H), 7.64 (m, 3H), 7.15 (d, J=7.3 Hz, 1H), 6.93 (m, 2H),6.80 (d, J=7.3 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.27 (m, 1H), 1.32 (d,J=6.3 Hz, 6H) ppm.

Preparation 92:N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-isopropoxy-3-pyridyl)-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1436)

N-((6-aminopyridin-2-yl)sulfonyl)-6-chloro-6′-isopropoxy-[2,3′-bipyridine]-3-carboxamide(0.050 g, 0.11mmol) and cesium floride (0.085 g, 0.56 mmol) werecombined in dimethyl sulfoxide (0.5 mL). The reaction mixture wasstirred at 150° C. for 16 hours. (4S)-2,2,4-trimethylpyrrolidine (0.0379g, 0.335 mmol) was added to the reaction mixture and the mixture wasstirred at 150° C. for 10 hours. The crude product was purified byreverse phase HPLC utilizing a gradient of 10 to 99% acetonitrile inwater to yieldN-[(6-amino-2-pyridyl)sulfonyl]-2-(6-isopropoxy-3-pyridyl)-64(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1436) (0.0026 g, 0.0050 mmol, 4.5%). ESI-MS m/z calc. 424.2,found 525.3 (M+1)⁺; Retention time: 1.89 minutes.

The following compounds can be synthesized using the proceduresdescribed herein

N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-fluoro-5-isobutoxy-phenyl)-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1409),

-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-fluoro-5-isobutoxy-phenyl)-6-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1385),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(6-isopropoxy-3-pyridyl)-6-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1491).

Preparation 93:N-[(6-amino-2-pyridyl)sulfonyl]-6-cyano-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1564)

[(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (4.186 mg, 0.005270 mmol),triisopropylphenyl)phenyl]phosphane (2.238 mg, 0.005270 mmol), Potassiumhexacyanoferrate(II) trihydrate (22.26 mg, 0.05270 mmol), andN-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 852) (44.7 mg, 0.1054 mmol) were added to a vial and the vialwas purged with nitrogen. Deoxygenated dioxane (500 μL) and a solutionof potassium carbonate (263.6 μL of 0.05 M, 0.01318 mmol) was added toreaction mixture, the head space was purged with nitorgen and the sealedvial was stirred at 100° C. for 1 hour. The crude product was purifiedby reverse phase HPLC utilizing a gradient of 10 to 99% acetonitrile inwater to yieldN-[(6-amino-2-pyridyl)sulfonyl]-6-cyano-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1564) (1.8 mg, 0.0043 mmol, 4.1%) ESI-MS m/z calc. 414.1474,found 415.2 (M+1)⁺; Retention time: 1.49 minutes.

Preparation 94:N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-hydroxy-pyridine-3-carboxamide(Compound 1430)

In a nitrogen purged flask,N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-methoxy-pyridine-3-carboxamide(Compound 1254) (17.5 mg, 0.0306 mmol) was dissolved in dichloromethane(1.577 mL). The mixture was cooled to −78° C., and tribromoborane (811.2mg, 306.14 of 1 M, 0.3061 mmol) was added to the reaction mixture in adropwise manner. The mixture was slowly warmed to room temperature. Themixture was stirred overnight at ambient temperature. The reactionmixture was added to ice ( 5 mL). The layers were separated, and theaqueous layer was extracted with dichloromethane. The combined organiclayers were dried over sodium sulfate, concentrated, and purified byreverse phase HPLC utilizing a gradient of 1-99% acetonitrile in 5 mMaqueous hydrochloric acid. The compound was further puried on silica gelusing dichloromethane as the eluent to yieldN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-hydroxy-pyridine-3-carboxamide(Compound 1430) (3.2 mg, 0.0057 mmol, 19%) as an off -white solid.ESI-MS m/z calc. 557.2108, found 558.3 (M+1)⁺, Retention time: 1.84minutes.

Preparation 95: 4-Bromo-2-(mesityloxy)benzoic acid Step 1:4-Bromo-2-(mesityloxy)benzonitrile

A mixture of 4-bromo-2-fluoro-benzonitrile (1.2 g, 6.0 mmol),2,4,6-trimethyiphenol (780 mg, 6.1 mmol), potassium carbonate (2.50 g,18.1 mmol), and dimethylsulfoxide (9.0 mL) were microwave irradiated at140° C. for 2 hours. Water (20 mL) was added and the resulting mixturewas stirred for 5 minutes. The resulting suspension was filtered and thesolid was washed with water and dried under vacuum at 50° C. for 16hours to yield 4-bromo-2-(mesityloxy)benzonitrile (1.8 g, 95%) as abrown solid. ¹H NMR (CDCl₃, 250 MHz): 7.50 (d, J=8.2 Hz, 1H), 7.20 (d,J=8.2 Hz, 1H), 6.94 (s, 2H), 6.61 (s, 1H), 2.33 (s, 3H), 2.10 (s, 6H)ppm.

Step 2: 4-Bromo-2-(mesityloxy)benzoic acid

4-bromo-2-(mesityloxy)benzonitrile (1.8 g, 9.0 mmol) was suspended inethanol (6 mL) and water (12 mL), containing sodium hydroxide (3.0 g, 75mmol). The mixture was stirred at 90° C. for 16 hours. Hydrochloric acid(6M, 13 mL) was added to the reaction mixture followed by water (20 mL)and the suspension was stirred for 10 minutes, filtered, and washed withwater and hthen hexanes to yield 4-bromo-2-(mesityloxy)benzoic acid asan off-white solid (1.7 g, 5.1 mmol, 57%). NMR (DMSO-d₆, 250 MHz): 7.74(d, J=8.2 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.01 (s, 2H), 6.41 (s, 1H),2.28 (s, 3H), 2.02 (s, 6H) ppm.

Preparation 96: 6-Methoxy-4-methylpyridine-2-sulfonamide Step 1:2-Benzylsulfanyl-6-chloro-4-methylpyridine

2,6-Dichloro-4-methyl-pyridine (4.74 g, 29.3 mmol) was dissolved intetrahydrofuran (47.40 mL) with phenylmethanethiol (3.634 g, 3.435 mL,29.26 mmol) and 2-methylpropan-2-olate (Sodium Ion (1)) (29.26 mL of 2M, 58.52 mmol) was added to the reaction mixture. The reaction wasstirred for 16 hours and partitioned between water and ethyl acetate.The organics were separated, washed with brine, dried over sodiumsulfate and evaporated. The crude material was used without fu rtherpurification. 2-Benzylsulfanyl-6-chloro-4-methyl-pyridine (6.91 g, 27.7mmol, 94.5%) ESI-MS m/z calc. 249.0379, found 250.0 (M+1) ; Retentiontime: 0.78 minutes.

Step 2: 6-Chloro-4-methylpyridine-2-sulfonamide

A biphasic mixture of 2-benzylsulfanyl-6-chloro-4-methyl-pyridine (6.87g, 27.5 mmol) in dichloromethane (41.22 mL), water (13.74 mL), andaqueous hydrochloric acid (2.751 mL of 1 M, 2.751 mmol) was cooled in asalt water ice bath. (Note: Aqueous hydrochloric acid is added to avoidan otherwise delayed exotherm upon the chlorine addition.). Chlorine(7.800 g, 110.0 mmol) was bubbled through the solution (3 times at 2minute intervals) over an hour. The reaction was stirred at 0° C. After1.5 hours (reaction monitored by UPLC) the reaction was added dropwiseto an ice bath cooled solution of ammonium hydroxide (41.32 mL of 28%w/v, 330.1 mmol). The reaction was warmed to room temperature andstirred for 15 minutes. The reaction mixture was partitioned betweenethyl acetate (60 mL) and water (20 mL). The organics were separated,and the aqueous layer was extracted twice with ethyl acetate (60 mLportions). The organics were combined, washed with brine, dried oversodium sulfate and evaporated. The resulting solid was triturated withdichloromethanr (30 mL) and filtered. The solid was washed with minimaldichloromethane to give 6-chloro-4-methyl-pyridine-2-sulfonamide as anoff white solid (3.18 g, 15.4 mmol, 56.0%) ¹H NMR (400 MHz, DMSO-d₆) δ7.78 (dd, J=1.3, 0.7 Hz, 1H), 7.66-7.63 (m, 1H), 7.59 (s, 2H), 2.45 (s,3H). ESI-MS m/z calc. 205.99167, found 206.9 (M+2)⁺; Retention time: 0.3minutes.

Step 3: 6-Methoxy-4-methylpyridine-2-sulfonamide

6-Chloro-4-methylpyridine-2-sulfonamide (500. mg, 2.42 mmol) wasdissolved in sodium methoxide in methanol (2.537 g, 2.615 mL of 25% w/v,12.10 mmol) and heated at 65° C. After 1 hour, all starting material wasgone and two products had formed. The reaction mixture was partitionedbetween ethyl acetate and a saturated aqueous ammonium chloridesolution. The organics were separated, washed with water, brine, driedover sodium sulfate and evaporated to dryness. The crude product waspurified by silica gel chromatography eluting with 0 to 100% ethylacetate in hexanes to give 6-methoxy-4-methylpyridine-2-sulfonamide (126mg, 0.623 mmol, 25.7%) ESI-MS m/z calc. 202.04121, found 203.0 (M+1)⁺;Retention time: 0.32 minutes.

Preparation 97: 6-Amino-4-methylpyridine-2-sulfonamide

6-Chloro-4-methylpyridine-2-sulfonamide (500. mg, 2.42 mmol) wasdissolved in aqueous ammonium hydroxide (3.029 mL of 28% w/v, 24.20mmol) and irradiated in a microwave reactor for 1 hour at 150° C. Thereaction was evaporated and the solid was washed with water and methanolto remove excess ammonium hydroxide. The resulting solid was a mixtureof product and starting material. The mixture was taken on to the nextstep without further purification..6-amino-4-methylpyridine-2-sulfonamide (200. mg, 1.07 mmol, 44.2%)ESI-MS m/z calc. 187.04155, found 188.0 (M+1)⁺; Retention time: 0.21minutes.

PREPARATION 98:4,4,5,5-Tetramethyl-2-(3,3,5,5-tetramethylcyclopenten-1-yl)-1,3,2-dioxaborolaneStep 1: 3,3,5-trimethyl-5-trimethylstannyl-cyclohexanone

To a stirring solution of trimethyl(trimethylstannyl)stannane (3.555 g,2.250 mL, 10.85 mmol) in tetrahydrofuran (50 mL) at −20° C. was addedmethyllithium (4.964 g, 6.781 mL of 1.6 M, 10.85 mmol) and the mixturewas stirred at −20° C. for 15minutes. Next the3,5,5-trimethylcyclohex-2-en-1-one (1.00 g, 7.24 mmol) was slowly addedand the reaction mixture was warmed to 0° C., stirred 30 minutes, andthen quenched with methanol (695.6 mg, 879.4 μL, 21.71 mmol). Thereaction mixture was warmed to room temperature and diluted with waterthen extracted twice with diethyl ether. The combined organic layerswere dried (sodium sulfate), filtered and concentrated to a yellow oilwhich was purified by silica gel chromatography using 100% hexanes aseluent followed by 100% dichloromethane as eluent to yield3,3,5-trimethyl-5-trimethylstannyl-cyclohexanone (2.01 g, 6.63 mmol,91.7%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) 2.59-2.45 (m, 1H),2.21-2.12 (m, 3H), 1.92 (d, J=14.2 Hz, 1H), 1.59 (d, J=14.2 Hz, 1H),1.28 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H), 0.13 (d, J=1.1 Hz, 1H), 0.07(s, 9H), 0.01 (d, J=1.1 Hz, 1H).

Step 2: 2,2,4,4-Tetramethylcyclopentanone

To a stirring solution of3,3,5-trimethyl-5-trimethylstannyl-cyclohexanone (4.17 g, 13.8 mmol) inthe dichloromethane (79.23 mL) under a nitrogen atmosphere at 0° C. wasadded (dropwise) tetrachlorotitanium (2.610 g, 2.183 mL, 13.76 mmol)giving a dark brown color on addition. Upon completion of addition thereaction mixture was a brown suspension which was stirred 20 minutes at0° C. and then quenched by the addition of a solution of saturatedaqueous sodium bicarbonate (Caution: Gas evolution, reaction becamebiphasic with a purple suspension as the aqueous layer). The resultingmixture was extracted twice with dichloromethane, dried (magnesiumsulfate), filtered and carefully concentrated to a clear oil. Purifiedby silica gel chromatography eluting with 100% giving2,2,4,4-tetramethylcyclopentanone (1.67 g, 11.9 mmol, 86.6%) as a clearoil.

Step 3:4,4,5,5-Tetramethyl-2-(3,3,5,5-tetramethylcyclopenten-1-yl)-1,3,2-dioxaborolane

To 2,2,4,4-tetramethylcyclopentanone (1.67 g, 11.9 mmol) was addedtetrahydrofuran (16.70 mL) and the reaction was chilled to −78° C. Thereaction was stirred for 10 minutes and lithium bis(trimethylsilyl)amide(14.29 mL of 1 M, 14.29 mmol) was added dropwise and the reaction wasallowed to stir at −78° C. for 1 hour.1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(5.105 g, 14.29 mmol) dissolved in tetrahydrofuran (12.5 mL) was addeddropwise and the reaction was allowed to warm to room temperature andstir 16 hours. The reaction was quenched with a saturated aqueoussolution of sodium chloride and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate and evaporated to an orangesyrup. The crude orange syrup was added to a mixture ofbis(pinacol)diboron (4.535 g, 17.86 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (871.5 mg, 1.191 mmol) and potassium acetate (3.507g, 35.73 mmol) in dimethylformamide (16.70 mL). The reaction was purgedwith nitrogen and heated to 65° C. for 16 hours. The reaction wasquenched with a saturated aqueous solution of sodium chloride andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and evaporated to dryness. The crude product was purified bysilica gel chromatography using a gradient from 100% hexanes to 40%ethyl acetate in hexanes giving4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclopenten-1-yl)-1,3,2-dioxaborolane(651 mg, 2.60 mmol, 21.8%) as a white solid.

PREPARATION 99:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Isomer 1) (Compound 2374) (Isomer 2) Step 1: ethyl2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate

2-Chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid(5.077 g, 15.53 mmol) was dissolved in ethyl alcohol (50.26 mL) andthionyl chloride (2.218 g, 1.360 mL, 18.64 mmol) was added dropwise. Theresulting solution was slowly heated to 76° C. (reflux) and stirred at76° C. for 5 hours. The brownish solution was concentrated to removesolvent. The crude residue was redissolved in ethyl acetate andextracted with saturated aqueous sodium bicarbonate. The aqueous phasewas extracted twice with ethyl acetate. The combined organic layers wereextracted with saturated aqueous brine, dried over sodium sulfate,concentrated and purified by silica gel chromatography using a gradientfrom 100% hexanes to 100% ethyl acetate giving ethyl2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate (3.64 g,10.3 mmol, 66.6%) as a white solid.

Step 2: Ethyl6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5,5-tetramethylcyclopenten-1-yl)pyridine-3-carboxylate

A mixture of ethyl2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate (841.8mg, 2.393 mmol),4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclopenten-1-yl)-1,3,2-dioxaborolane(598.7 mg, 2.393 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (525.3 mg, 0.7179 mmol), and sodium carbonate(760.9 mg, 7.179 mmol) in dioxane (10.77 mL) and water (1.196 mL) washeated in a sealed vessel at 150° C. for 16 hours. The reaction wasfiltered and the solids were washed with ethyl acetate. The extract wasevaporated and the residue was purified by silica gel chromatographyusing a gradient from 100% hexanes to 25% ethyl acetate in hexanes togive ethyl6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5,5-tetramethylcyclopenten-1-yl)pyridine-3-carboxylate(460.3 mg, 1.047 mmol, 43.75%) as a light yellow solid.

Step 3:6-(3-Fluoro-5-isobutoxy-phenyl)-2-(3,3,5,5-tetramethylcyclopenten-1-yl)pyridine-3-carboxylicacid

A solution of ethyl6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5,5-tetramethylcyclopenten-1-yl)pyridine-3-carboxylate(460.3 mg, 1.047 mmol) and sodium hydroxide (2.617 mL of 1 M, 2.617mmol) in tetrahydrofuran (2.606 mL) and water (2.606 mL) was stirred at50° C. for 6.5 hours. The reaction was cooled to room temperature andthen neutralized with 1M hydrochloric acid and extracted twice withethyl acetate. The combined extracts were dried over sodium sulfate andevaporated to give6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5,5-tetramethylcyclopenten-1-yl)pyridine-3-carboxylicacid (389.1 mg, 0.9455 mmol, 90.32%) as yellow needles.

Step 4:6-(3-Fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxylicacid

A mixture of6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5,5-tetramethylcyclopenten-1-yl)pyridine-3-carboxylicacid (389.1 mg, 0.9455 mmol), palladium hydroxide (79.67 mg, 0.5673mmol) and ammonium formate (1.192 g, 18.91 mmol) in ethanol (10 mL) werecombined in a microwave vial and heated to 85° C. for 3hours. Thereaction mixture was cooled to room temperature, uncapped, ammoniumformate (1.192 g, 18.91 mmol) and palladium hydroxide (79.67 mg, 0.5673mmol) were added, nitrogen was bubbled through the solution for 2minutes, and the vial was capped and returned to the microwave reactorat 85° C. for 4 additional hours. The reaction was filtered throughcelite eluting with methanol and concentrated under reduced pressure.The mixture was then diluted with 1N aqueous hydrochloric acid andwashed with twice with ethyl acetate. The organic layers were combined,dried (sodium sulfate), filtered and concentrated to a clear oil withsome white solid present. The crude material was purified by silica gelchromatography using a gradient from 100% dichloromethane to 20%methanol in dichloromethane followed by 20% methanol in ethyl acetategiving6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxylicacid (52.3 mg, 0.126 mmol, 13.4%) as a white solid.

Step 5:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Isomer 1) (Compound 2374) (Isomer 2)

A solution of6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxylicacid (52.0 mg, 0.126 mmol) and carbonyl diimidazole (30.58 mg, 0.1886mmol) in dimethylformamide (0.5 mL) was stirred at 45° C. for 90minutes. A separate solution of 6-aminopyridine-2-sulfonamide (43.54 mg,0.2514 mmol) and sodium hydride (10.06 mg, 0.2514 mmol) indimethylformamide (0.5 mL) which was stirred at 45° C. for 45 minuteswas then added and the resulting mixture was stirred at 45° C. for2hours. The reaction was filtered and purified using a reverse phaseHPLC-MS method using a Luna C18 (2) column (75×30 mm, 5 μm particlesize) sold by Phenomenex (pn: 00C-4252-U0-AX), and a dual gradient runfrom 1 to 99% mobile phase B over 15.0 minutes (mobile phase A=H₂O (5 mMHCl), mobile phase B =acetonitrile, flow rate=50 mL/min, injectionvolume=950 μL and column temperature=25° C.) givingN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Isomer 1) (Compound 2374) (Isomer 2) hydrochloride (51mg, 0.084 mmol, 67%) as an off-white solid ¹H NMR (400 MHz, DMSO-d₆) δ12.63 (s, 1H), 7.91 (dd, J=20.4, 8.2 Hz, 2H), 7.66 (t, J=7.9 Hz, 1H),7.57 (s, 1H), 7.51 (d, J=9.8 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 6.93 (d,J=10.7 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.51 (s, 2H), 3.86 (d, J=6.6 Hz,2H), 3.58 (dd, J=12.2, 6.5 Hz, 1H), 2.55 (d, J=12.3 Hz, 1H), 2.06 (dt,J=13.2, 6.6 Hz, 1H), 1.63 (dd, J=12.4, 6.4 Hz, 1H), 1.50 (d, J=13.0 Hz,1H), 1.39 (d, J=12.9 Hz, 1H), 1.15 (s, 3H), 1.08-0.93 (m, 9H), 0.80 (s,3H), 0.69 (s, 3H). ESI-MS m/z calc. 568.25195, found 569.3 (M+1)⁺;Retention time: 2.4 minutes.

PREPARATION 100:4,4,5,5-tetramethyl-2-[(5S)-3,3,5-trimethylcyclohexen-1-yl]-1,3,2-dioxaborolaneStep 1: (5R)-3,3,5-Trimethylcyclohexanone

To a round bottom flask purged with nitrogen was added copper (II)acetate (14.53 mg, 0.08000 mmol),[(4S)-4-[5-bis(3,5-ditert-butyl-4-methoxy-phenyl)phosphanyl-1,3-benzodioxol-4-yl]-4,5,6,7-tetrahydro-1,3-benzodioxol-5-yl]-bis(3,5-ditert-butyl-4-methoxy-phenyl)phosphane(47.34 mg, 0.04000 mmol), and toluene (27.64 mL). The reaction wasstirred at room temperature for 90 minutes. Polymethylhydrosiloxane (4.8mL) was added and the reaction was allowed to stir at room temperaturefor 30 minutes. 3,5,5-Trimethylcyclohex-2-en-1-one (5.528 g, 6.009 mL,40.00 mmol) was then added dropwise and the reaction was allowed to stirfor 90 minutes at room temperature. The reaction was poured into asolution of 3M sodium hydroxide and allowed to stir vigorously for 2hours. The crude reaction was extracted with ethyl acetate and driedover sodium sulfate. The solvent was removed and the crude product wastaken onto the next step without further purification to give(5R)-3,3,5-trimethylcyclohexanone (5.1 g, 36 mmol, 91%) ESI-MS m/z calc.140.12012, found 141.2 (M+1)⁺; Retention time: 1.44 minutes was a paleoil.

Step 2:4,4,5,5-tetramethyl-2-[(5S)-3,3,5-trimethylcyclohexen-1-yl]-1,3,2-dioxaborolane

To crude (5R)-3,3,5-trimethylcyclohexanone (2.85 g, 20.3 mmol) was addedtetrahydrofuran (28.50 mL) and the reaction was chilled to −78° C. Thereaction was stirred for 10 minutes and lithium bis(trimethylsilyl)amide(24.38 mL of 1 M, 24.38 mmol) was added dropwise and the reaction wasallowed to stir at −78° C. for 1 hour.1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(8.710 g, 24.38 mmol) dissolved in tetrahydrofuran (20 mL) was addeddropwise and the reaction was allowed to warm to room temperature andstir for 16 hours. The reaction was quenched with brine and extractedwith ethyl acetate. The organic layer was dried over sodium sulfate andevaporated to a yellow oil. The crude vinyl triflate was used in thenext step without further purification. The crude vinyl triflate wasadded to a mixture of bis(pinacol)diboron (7.740 g, 30.48 mmol),bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1.487 g, 2.032 mmol), potassium acetate (5.983 g, 60.96mmol) in N,N-dimethylformamide (28.50 mL). The reaction was purged withnitrogen and heated to 65° C. for 16 hours. The reaction was quenchedwith brine and extracted with ethyl acetate. The organic layer was driedover sodium sulfate and evaporated. The crude product was purified bysilica gel chromatography utilizing a gradient of 0 to 40% ethyl acetatein hexanes to yield4,4,5,5-tetramethyl-2-[(5S)-3,3,5-trimethylcyclohexen-1-yl]-1,3,2-dioxaborolane(2.2 g, 8.8 mmol, 43%) as a mixture of regioisomers ESI-MS m/z calc.250.2104, found 251.6 (M+1)⁺; Retention time: 2.17 minutes

PREPARATION 101:N-[(6-amino-2-pyridyl)sulfonyl]-6-[(1S,2S)-2-(methoxymethyl)cyclopropyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1575) Step 1:N-[(6-amino-2-pyridyl)sulfonyl]-6-[(1S,2S)-2-(methoxymethyl)cyclopropyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1575) andN-[(6-amino-2-pyridyl)sulfonyl]-6-[(1R,2R)-2-(methoxymethyl)cyclopropyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

To a microwave vial was addedN-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 852) trifluoroacetic acid salt (100 mg, 0.186 mmol),[1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride (6.3 mg, 0.0093 mmol) and dioxane (600 μL). The reaction waspurged with nitrogen for 2 minutes and trans2-[(1S,2S)-2-(methoxymethyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(68.99 mg, 0.325 mmol) was added followed by an aqueous 2M solution ofpotassium carbonate (279 μL of 2 M, 0.558 mmol). Then the reaction wasirradiated to 120° C. over 16 hours in the microwave reactor. Thereaction mixture was allowed to cool, filtered and then purifieddirectly by reverse-phase preparative chromatography utilizing a C18column and HPLC-MS method 1 to 99 acetonitrile in water containing 5 mMhydrochloric acid to afford two compounds. Compound 1 (2.26 mg, 0.0044mmol, 2.39%) ESI-MS m/z calc. 473.2097, found 474.2 (M+1)⁺; Retentiontime: 1.13 minutes. Compound 2 (0.86 mg, 0.0018 mmol, 0.97%) ESI-MS m/zcalc. 473.2097, found 474.2 (M+1)⁺; Retention time: 1.26 minutes as alight yellow solid.

Preparation 102:N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

Step 1:6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxylicacid

6-chloro-2-fluoro-pyridine-3-carboxylic acid (1.50 g, 8.545 mmol) and(4S)-2,2,4-trimethylpyrrolidine (Hydrochloric Acid) (1.534 g, 10.25mmol) were combined in DMSO (4.500 mL). Potassium carbonate (2.362 g,17.09 mmol) was added. Note: Substantial bubbling was observed uponmixing. The reaction mixture was sealed and heated at 90° C. overnight.The reaction mixture was diluted with EtOAc (50 mL) and washed withaqueous 0.5 N HCl. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to a yellow oil. Toremove any residual solvents, the oil was subjected to a stream ofnitrogen gas for 1 hour, resulting in a crystalline solid. The productwas used in the next step without further purification. ESI-MS m/z calc.268.09787, found 269.2 (M+1)⁺; Retention time: 1.49 minutes

Step 2: tert-butylN-[(3S)-1-[[6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carbonyl]sulfamoyl]pyrrolidin-3-yl]carbamate

6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxylicacid (1.61 g, 5.99 mmol) was dissolved in dichloromethane (8 mL), warmedto 40° C. and N-(oxomethylene)sulfamoyl chloride (1.017 g, 625.5 μL,7.189 mmol) was added. Note: Substantial bubbling was observed duringaddition. After 3 minutes of stirring at 40° C., additionaldichloromethane (10 mL) was added followed by tert-butylN-[(3S)-pyrrolidin-3-yl]carbamate (2.80 g, 15.0 mmol). Bubbling wasobserved. After overnight stirring at 40° C., the reaction mixture wasdiluted with EtOAc (75 mL) and washed with water and brine. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The product was isolated by silica gel columnchromatography: 0 to 40% EtOAc/hexane gradient on a 80 gram silica gelcolumn tert-butylN-[(3S)-[[6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carbonyl]sulfamoyl]pyrrolidin-3-yl]carbamate(965 mg, 1.87 mmol, 31.2%) was obtained as a lightly brown foamingsolid. ¹H NMR (400 MHz, DMSO-d₆) 11.92 (s, 1H), 7.62 (d, J=7.9 Hz, 1H),7.18 (s, 1H), 6.61 (d, J=7.9 Hz, 1H), 3.96 (s, 1H), 3.65-3.45 (m, 3H),3.14 (dd, J=9.7, 5.9 Hz, 1H), 3.03 (t, J=10.3 Hz, 1H), 2.97-2.85 (m,1H), 2.33 (s, 1H), 2.04 (dd, J=12.7, 5.7 Hz, 1H), 1.92 (dd, J=11.4, 5.1Hz, 1H), 1.78 (dd, J=12.6, 6.9 Hz, 1H), 1.54 (d, J=6.1 Hz, 6H), 1.38 (s,9H), 1.01 (d, J=6.3 Hz, 3H), 0.83 (s, 1H). ESI-MS m/z calc. 515.1969,found 516.4 (M+1)⁺; Retention time: 0.77 minutes.

Step 3:N-[(3S)-3-aminopyrrolidin-1-yl]sulfonyl-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

tert-butylN-[(3S)-1-[[6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carbonyl]sulfamoyl]pyrrolidin-3-yl]carbamate(100 mg, 0.1938 mmol) was dissolved in CH2Cl2 (1 mL), and TFA (1 mL,12.98 mmol) was added. The solution was allowed to stir at roomtemperature for 30 minutes. Volatiles were removed under reducedpressure. The crude product was used in the next step without furtherpurification.

Preparation 103:N-[(6-amino-2-pyridyl)sulfonyl]-[1-(tert-butylcarbamoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2568)

To a stirred solution ofN-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2,3,6-tetrahydropyridin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Hydrochloric Acid (2)) (27 mg, 0.037 mmol) in anhydrous dichloromethane(1.0 mL), triethyl amine (50 μL, 0.3587 mmol) and2-isocyanato-2-methyl-propane (8.0 mg, 0.081 mmol) were added at 0° C.under nitrogen. The yellow solution was stirred at ambient temperaturefor 2 hours. The volatiles were removed under reduced pressure and theresidue was purified by reverse-phase HPLC to furnishN-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(tert-butylcarbamoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2568) (Hydrochloric Acid (1)) (9.2 mg, 0.015 mmol, 41%) ESI-MSm/z calc. 569.27844, found 570.4 (M+1)⁺; Retention time: 1.3 minutes

The following compounds can be synthesized using the proceduresdescribed herein

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[1-(cyclohexylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2520)

Preparation 104:N-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(2,2-dimethylbutanoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2612)

To a stirred solution ofN-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2,3,6-tetrahydropyridin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Hydrochloric Acid (2)) (27 mg, 0.037 mmol) in anhydrous dichloromethane(1.0 mL), triethyl amine (50. μL, 0.36 mmol) and 2,2-dimethylbutanoylchloride (11 mg, 0.082 mmol) were added at 0° C. under nitrogen. Theyellow solution was stirred at ambient temperature for 2 hours. Thevolatiles were removed under reduced pressure and the residue waspurified from reverse-phase HPLC to furnishN-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(2,2-dimethylbutanoye-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2612) (Hydrochloric Acid (1)) (6.7 mg, 0.011 mmol, 27%) ESI-MSm/z calc. 568.2832, found 569.7 (M+1)⁺; Retention time: 1.44 minutes

The following compounds can be synthesized using the proceduresdescribed herein

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(3-chlorobenzoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1984),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(1-piperidylsulfonyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1942),-   N-[[6-[(2-phenylacetyl)amino]-2-pyridyl]sulfonyl]-6-[1-(2-phenylacetyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2243),-   isopropyl    N-[6-[[6-(1,2,3,6-tetrahydropyridin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]carbamate    (Compound 2624),-   isopropyl    5-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate    (Compound 2622),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(3,3-dimethylbutanoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2650),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[1-(2-cyclohexylacetyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2596),-   isopropyl    4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate    (Compound 2027),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[1-(2-phenylacetyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2417),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[1-(3,3-dimethylbutanoyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2344),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(2-cyclohexylacetyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2633) and,-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isobutylsulfonyl-3,6-dihydro-2H-pyridin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1882)

Preparation 105:N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-[(3R)-tetrahydrofuran-3-yl]oxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2281)

To a 4 mL vial was added NaH (10. mg, 0.25 mmol),(3R)-tetrahydrofuran-3-ol (27.63 mg, 25.19 μL, 0.3136 mmol), and DMSO(800 4). The mixture was stirred at ambient temperature for 2 minutes.N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Hydrochloric Acid (1)) (30. mg, 0.063 mmol) was then added to the vialand the reaction was stirred at 150° C. for 2 hours. The reactionmixture was filtered and purified by preparative HPLC (1-99%acetonitrile over 30 minutes with 5 mM HCl modifier) to giveN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-[(3R)-tetrahydrofuran-3-yl]oxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2281) (Hydrochloric Acid (1)) (9 mg, 0.02 mmol, 30%) NMR (400MHz, DMSO-d₆) δ 12.29 (s, 1H), 7.66-7.57 (m, 2H), 7.17 (d, J=7.3 Hz,1H), 6.66 (d, J=8.3 Hz, 1H), 6.41 (s, 2H), 5.55-5.48 (m, 1H), 3.94-3.83(m, 2H), 3.83-3.76 (m, 2H), 2.56 (d, J=10.6 Hz, 1H), 2.44 (t, J=8.7 Hz,1H), 2.32-2.16 (m, 1H), 2.10-2.02 (m, 1H), 1.84 (dd, J=11.8, 5.6 Hz,1H), 1.53 (s, 3H), 1.44 (s, 3H), 1.37 (t, J=12.0 Hz, 1H), 0.85 (d, J=6.3Hz, 3H). ESI-MS m/z calc. 493.1795, found 494.3 (M+1)⁺; Retention time:1.08 minutes

The following compounds can be synthesized using the proceduresdescribed herein

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[(1R)-1,2-dimethylpropoxy]-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2020),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-cyclohexylethoxy)-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1730),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-[(3S)-tetrahydrofuran-3-yl]oxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2056),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-cyclopentylethoxy)-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1966),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-(1-tetrahydropyran-4-ylethoxy)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1891),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(cyclopentoxy)-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2100),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(2,2-dimethylmorpholin-4-yl)-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2586), and-   N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-1-(4-pyridyl)ethoxy]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2212)

Preparation 106:6-tert-butyl-N-[[6-[(4-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2724) (Isomer 1) (Compound 2428) (Isomer 2)

6-(tert-butyl)-N-((6-chloropyridin-2-yl)sulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide(100. mg, 0.215 mmol) and (4-methoxyphenyl)methanol (59.6 mg, 0.431mmol) were dissolved in anhydrous anhydrous dimethyl sulfoxide (1 mL),and then cesium carbonate (210 mg, 0.645 mmol) was added to the reactionmixture The resulting mixture was heated at 130° C. for 24 hours andcooled to room temperature. Water (10 mL) and aqueous hydrogen chloridesolution (1N) was added until pH value of solution was around 2.Reaction solution was extracted with ethyl acetate, and the extract waswashed with brine, dried over sodium sulfate and filtered. Solvents wereremoved under the reduced pressure. The residue obtained was purified byreverse-phase HPLC utilizing a gradient of 0.1% trifluoroacetic acid inwater and 0.1% trifluoroacetic acid in acetonitrile. Factions werelyophilized to afford6-tert-butyl-N-[[6-((4-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2724) (Isomer 1) (Compound 2428) (Isomer 2) (35.2 mg, 0.0621mmol, 28.9%). MS (ESI, m/z): [M+H]⁺567.3.

The following compounds can be synthesized using the proceduresdescribed herein

-   N-[[6-[2-(4-fluorophenyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1704),-   N-[[6-(3-phenylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1708),-   N-[[6-[methyl(propyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1711),-   N-[[6-[(4-methoxyphenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1717),-   N-[(6-tert-butoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1718),-   N-[[6-(3-methoxy-5-methyl-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1719),-   N-[[6-(2-cyanophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1720),-   N-[[6-(4-isopropylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1722),-   N-[[6-(4-cyclopentylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1733),-   N-[[6-(pyrrolidin-3-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1734),-   N-[[6-(4-acetyl-2-methoxy-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1744),-   N-[[6-(3,5-dimethyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1749),-   N-[[6-(1-naphthyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1751),-   N-[(6-prop-2-ynoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1753),-   N-[[6-(3-phenyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1755),-   N-[[6-(4-tert-butylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1756),-   N-[[6-[4-(dimethylamino)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1757),-   N-[[6-(3,4-dimethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1761),-   N-[[6-(tetrahydrofuran-2-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1764),-   N-[[6-(cyclohexylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1767),-   N-[[6-[(2,5-difluorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1770),-   tert-butyl    4-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]piperazine-1-carboxylate    (Compound 1773),-   N-[[6-(1,3-benzothiazol-6-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1775),-   N-[[6-(3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1776),-   N-[[6-[(5-phenylisoxazol-3-yl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1777),-   N-[[6-[(3-chloro-4-methoxy-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1778),-   N-[[6-(3-ethynylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1782),-   N-[[6-(2,4,5-trifluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1796),-   N-[[6-[(2-fluorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1798),-   N-[[6-(2-cyclohexylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1800),-   N-[[6-[3-(methoxymethyl)-1-piperidyl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1805),-   N-[[6-(2,4-dichlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1806),-   N-[[6-(4-fluorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1813),-   N-[[6-(1,3-benzodioxol-5-ylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1814),-   N-[[6-[4-(2-pyridyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1816),-   N-[[6-(1H-indol-5-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1823),-   N-[[6-(8-quinolylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1826),-   N-[[6-[benzyhl)ethyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1827),-   N-[[6-(3-ethoxyl)phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1828),-   N-[[6-(3-chloro-4-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1831),-   N-[[6-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1833),-   N-[[6-(cyclopentoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1834),-   N-[(6-isoindolin-2-yl-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1838),-   N-[[6-(3-chloroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1841),-   N-[[6-[(1R)-1-phenylethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1842),-   N-[[6-[(4-ethyl-2-pyridyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1862),-   N-[[6-(thiazol-2-ylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1865),-   N-[[6-[ethyl(2-methoxyethyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1870),-   N-[[6-(2-chloroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1872),-   N-[[6-(3,4-dihydro-2H-pyran-2-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1874),-   N-[[6-(7-quinolyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1875),-   N-[[6-[(1-acetylindolin-5-yl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1877),-   N-[[6-[3-(N-methylanilino)propylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1879),-   N-[[6-[(E)-but-2-enoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1881),-   N-[[6-(3-methylcyclopentoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1884),-   N-[[6-(p-tolylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1892),-   N-[[6-(2-methylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1898),-   N-[[6-[(2-chloro-4-fluoro-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrradin-1-yl)pyridine-3-carboxamide    (Compound 1899),-   N-[[6-(4-isopropylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1902),-   N-[[6-(1-phenylethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1905),-   N-[[6-(2,3-dichloroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1906),-   N-[[6-(cyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1908),-   N-[[6-(indan-5-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1909),-   N-[[6-(1-phenylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1917),-   N-[[6-(1-cyclohexylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1919),-   N-[(6-(4-ethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1924),-   N-[[6-(3-tert-butylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1926),-   N-[[6-[(2,4-dichlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1929),-   N-[[6-(azepan-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1932),-   N-[[6-(3-isoquinolylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1933),-   N-[[6-(1-methylcyclopentoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1936),-   N-[[6-[4-(1,3-dioxolan-2-ylmethyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1937),-   N-[[6-(benzylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1938),-   N-[[6-(tetrahydropyran-2-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1939),-   N-[[6-[(3-methoxyphenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1940),-   N-[[6-(2-chloro-5-fluoro-amino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1941),-   N-[[6-(3-acetylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1949),-   N-[[64[3-(trifluoromethyl)phenyl]methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1953),-   N-[(6-tetralin-5-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1955),-   N-[[6-[(5-chloro-3-pyridypoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1957),-   N-[[6-(2-methoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1959),-   N-[[6-[(2-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1965),-   N-[[6-[(2,4-dichlorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1968),-   N-[[6-[(4-tert-butylcyclohexyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1971),-   N-[[6-[(3-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1972),-   N-[[6-[4-(trifluoromethoxy)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1977),-   N-[[6-[methyl(phenethyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1978),-   N-[[6-[(2-chlorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1983),-   N-[[6-(4-pentylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1985),-   N-[[6-(1,3-dihydrobenzo[de]isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1986),-   N-[[6-(4-phenyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1987),-   N-[[6-(3-methylcyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1988),-   N-[[6-(2-quinolyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1989),-   N-[[6-(3-thienylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1992),-   N-[[6-[[(1R)-1-cyclohexylethyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1996),-   N-[[6-[(6-methylcyclohex-3-en-1-yl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2001),-   N-[[6-(1H-indol-5-yloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2003),-   N-[[6-(2-thienylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2004),-   N-[[6-[methyl-[2-(3-pyridyl)ethyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2005),-   N-[(6-(3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2011),-   N-[[6-[[3-(dimethylamino)phenyl]methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2012),-   N-[[6-(1,3-benzodioxol-5-yloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2013),-   N-[[6-(2-fluorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2015),-   N-[[6-(2-cyclohexylpropoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2019),-   N-[[6-(4-phenylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2023),-   N-[[6-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2024),-   N-[[6-(3,3-dimethylbutoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2025),-   N-[[6-(cyclopentylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2026),-   N-[[6-(3-methyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2030),-   N-[[6-(tetrahydropyran-4-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2032),-   N-[[6-(3,3-dimethylcyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2038),-   N-[[6-(3,4-dimethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2041),-   N-[[6-[cyclopropylmethyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2044),-   N-[[6-[1-(1-naphthyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2049),-   N-[[6-(cyclopentylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2053),-   N-[[6-[2-(trifluoromethyl)pyrrolidin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2055),-   N-[[6-(1-methylcycloheptoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2057),-   N-[[6-(1,7,7-trimethylnorbornan-2-yl)oxy-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2059),-   ethyl    3-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]benzoate    (Compound 2060),-   N-[[6-(3,4-dichlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2061),-   N-[[6-[(3-chlorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2064),-   N-[[6-(2-pyridylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2068),-   N-[[6-[2-(4-methoxyphenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2072),-   N-[[6-(5-quinolylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2074),-   N-[(6-isopentyloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2075),-   N-[[6-(4-cyanophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2076),-   N-[[6-[(3S)-1-benzylpyrrolidin-3-yl]oxy-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2078),-   N-[[6-[(4-methyl-2-pyridyl)amino]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2082),-   N-[[6-(2-tert-butylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2083),-   N-[[6-[4-(1-piperidyl)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2087),-   N-[[6-[(2-methoxyphenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2090),-   N-[[6-(2-phenylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2094),-   N-[[6-(3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2098),-   N-[[6-[(2,4-difluorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2099),-   N-[[6-(4-fluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2102),-   N-[[6-(2,4,6-trifluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2106),-   N-[[6-(4-benzyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2107),-   N-[[6-(3-isopropylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2108),-   N-[[6-[(1S,2S)-2-methylcyclopentoxyl-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2109),-   N-[[6-[(1-phenylpyrazol-4-yl)methoxy]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2111),-   N-[[6-(2,3-dihydro-1,4-benzodioxin-3-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2115),-   N-[[6-(3-methylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2116),-   N-[[6-[(4-pyrazol-1-ylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2118),-   N-[[6-(4-phenylbutylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2119),-   ethyl    4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]benzoate    (Compound 2122),-   N-[[6-(3-benzylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2123),-   N-[[6-(1,1-dimethylbutoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2130),-   N-[[6-(tetrahydrofuran-2-ylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2131),-   N-[[6-(3-methoxypropylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2135),-   N-[[6-(1-naphthylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2136),-   N-[[6-(2-methyl-2-pyrrol-1-yl-propoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2137),-   methyl    6-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]pyridine-3-carboxylate    (Compound 2140),-   N-[[6-(3-tert-butylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2142),-   N-[[6-[3-(trifluoromethoxy)anilino]-2-pyridylisulfonyl[-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2143),-   N-[[6-(4-chlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2145),-   N-[[6-[2-(2-thienyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2146),-   N-[(6-cyclohex-2-en-1-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2147),-   N-[[6-(2-naphthylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2151),-   N-[[6-(3-methoxy-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2152),-   N-[[6-[(4,6-dimethyl-2-pyridyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2160),-   N-[[6-[2-(3-thienyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2161),-   N-[[6-(3-chloro-2-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2165),-   N-[[6-(3,3-difluoropyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2166),-   N-[(6-butoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2167),-   N-[[6-[(3-methoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2168),-   N-[[6-(1,3-benzodioxol-5-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2169),-   N-[[6-(4-isopropylcyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2173),-   N-[[6-[4-(4-pyridylmethyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2175),-   N-[[6-(3-chloro-5-cyano-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2177),-   N-[[6-(2,5-dimethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2179),-   N-[[6-(2-thienylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2181),-   N-[[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2182),-   N-[[6-[(1S)-1-phenylethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2186),-   N-[[6-[(4-isopropylphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2187),-   N-[[6-(cyclobutylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2188),-   N-[[6-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2190),-   N-[[6-[(1-methylindol-5-yl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2193),-   N-[[6-(1-methylbutylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2197),-   N-[[6-[(2-methyl-1,3-benzothiazol-5-yl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2198),-   N-[[6-(isopropylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2200),-   N-[[6-(cyclooctylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2202),-   N-[[6-(2-phenoxyethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2206),-   N-[[6-(4-phenylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2208),-   N-[(6-decalin-2-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2211),-   N-[[6-(4-ethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2214),-   N-[[6-(2,4-dichloroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2217),-   N-[[6-[(2-methylcyclohexypamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2218),-   N-[[6-[1-(methoxymethyl)propylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2221),-   N-[[6-[4-(1-methylbutyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2226),-   N-[[6-(2,3-dimethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2233),-   N-[[6-(4-methoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2239),-   N-[[6-(1,3-benzodioxol-4-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2249),-   N-[[6-(cyclohexylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2250),-   tert-butyl    2-[methyl-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]acetate    (Compound 2251),-   N-[[6-(cycloheptoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2252),-   ethyl    4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyliamino]piperidine-1-carboxylate    (Compound 2253),-   N-[[6-(4-pyrazin-2-ylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2254),-   N-[(6-indolin-1-yl-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2255),-   N-[[6-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2260),-   N-[[6-[[2-(trifluoromethyl)phenyl]methoxyl-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2261),-   N-[[6-[2-(4-chlorophenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2262),-   N-[[6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2263),-   N-[[6-[(3-chlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2264),-   N-[[6-(1-naphthylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2270),-   N-[[6-[(2-chlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2273),-   N-[[6-(5-isoquinolylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2274),-   N-[[6-(3,5-difluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2282),-   N-[[6-[4-(6-methyl-2-pyridyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2285),-   N-[[6-[(4-tert-butylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2286),-   N-[[6-[4-(trifluoromethyl)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2292),-   N-[[6-(3,5-dimethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2293),-   N-[[6-[(6-methyl-2-pyridyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2294),-   N-[[6-(3-benzyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2297),-   N-[[6-(2-chlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2298),-   N-[[6-[(3-cyanophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2299),-   N-[[6-(2-ethylbutylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2305),-   N-[[6-[butyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2307),-   N-[[6-(2-furylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2308),-   N-[[6-(2,6-dimethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2309),-   N-[[6-[(2-methoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2310),-   N-[[6-(4-aminophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2314),-   N-[[6-(3-cyano-4-fluoro-anilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2316),-   N-[(6-cyclopent-3-en-1-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2317),-   N-[[6-[[(1R)-1,2-dimethylpropyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2318),-   N-[[6-(3-methylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2320),-   (3S)-2-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]-3,4-dihydro-1H-isoquinoline-3-carboxylic    acid (Compound 2321),-   N-[[6-(2-methylmorpholin-4-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2324),-   N-[[6-(4-acetylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2328),-   N-[[6-(2-tetrahydropyran-4-ylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2329),-   N-[[6-(4-methyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2330),-   N-[[6-(3-fluorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2332),-   N-[[6-(8-quinolyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2333),-   tert-butyl    N-[4-[4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]carbamate    (Compound 2335),-   N-[[6-(4-methylcyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2336),-   N-[[6-(1H-indol-4-yloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2338),-   N-[[6-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2340),-   N-[[6-(3,4-difluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2341),-   N-[[6-(cyclopropylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2342),-   N-[[6-[2-methoxyethyl(propyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2343),-   N-[[64isopentyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2346),-   N-[[6-(2,2-difluoroethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2350),-   N-[[6-(3-isopropoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2353),-   N-[[6-(2-ethoxyethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2354),-   N-[[6-(3,5-dimethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2357),-   N-[[6-[2-(2-pyridyl)ethylamino]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2359),-   N-[[6-[[6-(trifluoromethyl)-2-pyridyl]methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2365),-   N-[[6-(cyclobutoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2371),-   N-[[6-[(3-chlorophenyl)methyl-methyl-amino]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2378),-   N-[[6-[3-(trifluoromethyl)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2381),-   N-[[6-(3,4-dihydro-2H-quinolin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2382),-   N-[[6-[4-(2-dimethylaminoethyl)-1-piperidyl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2383),-   N-[[6-(5-chloroindolin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2385),-   N-[[6-(3-acetamidoanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2387),-   N-[[6-(1H-indazol-5-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2389),-   N-[[6-[(2,6-dichlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2390),-   N-[[6-(m-tolylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2391),-   N-[[6-[(3S)-3-fluoropyrrolidin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2393),-   N-[(6-(tetrahydrofuran-3-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2396),-   N-[[6-[2-(trifluoromethyl)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2397),-   tert-butyl    N-methyl-N-[2-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]ethyl]carbamate    (Compound 2400),-   N-[[6-[(3,4-dichlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2402),-   N-][6-[(1-benzylpyrrolidin-3-yl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2407),-   N-[[6-[1-(2-fluorophenyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2408),-   N-[[6-[(3-fluorophenyl)methoxyl-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2409),-   N-[[6-(2,2-dimethylpropoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2412),-   N-[[6-[(4-isopropylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2415),-   N-[[6-[(6-methoxy-2-pyridyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2420),-   N-[[6-[(3,5-difluorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2421),-   N-[[6-(4-hexylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2423),-   N-[[6-[(4-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2428),-   N-[(6-methoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2430),-   N-[[6-(3-acetamidophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2433),-   N-[[6-[(1-methylcyclopropyemethoxy]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2434),-   tert-butyl    N-[4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]cyclohexyl]carbamate    (Compound 2439),-   N-[[6-(4-imidazol-1-ylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2441),-   methyl    1-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]piperidine-4-carboxylate    (Compound 2442),-   N-[[6-[3-(dimethylamino)phenoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2443),-   N-[[6-(3-quinolylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2449),-   N-[[6-[2-(4-piperidyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2452),-   N-[[6-(4-fluoro-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2453),-   N-[[6-(4-methylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2460),-   N-[[6-(3-chlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2461),-   N-[[6-[(3,5-difluorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2462),-   N-[(6-morpholino-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2464),-   N-[[6-[2-(3-methoxyphenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2465),-   N-[[64[6-(trifluoromethyl)-3-pyridyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2466),-   N-[[6-[(1R)-1-methyl-2-phenyl-ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2470),-   N-[[6-[6-(trifluoromethyl)-3-pyridyl]methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2476),-   N-[[6-(3-cyanoanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2484),-   N-[[6-(2-isopropylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2486),-   ethyl    1-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]piperidine-4-carboxylate    (Compound 2488),-   methyl    3-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]benzoate    (Compound 2493),-   tert-butyl    3-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propanoate    (Compound 2495),-   N-[[6-[2-(p-tolyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2502),-   N-[[6-(5-chloro-2-methoxy-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2503),-   N-[[6-[4-(2-pyridylmethyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2504),-   methyl    4-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]piperazine-1-carboxylate    (Compound 2506),-   N-[[6-(3-furylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2507),-   N-[(6-phenoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2509),-   N-[[6-(2,6-difluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2513),-   N-[[6-[3-(dimethylamino)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2517),-   N-[[6-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2518),-   N-[[6-(1-oxotetralin-6-yl)oxy-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2523),-   N-[[6-[(4-fluorophenyl)methoxy]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2524),-   N-[[6-(3-ethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2526),-   N-[(6-propoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2528),-   N-[[6-(3-butoxypropylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2529),-   N-[[6-[4-(diethylamino)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2531),-   N-[[6-[(3,4-difluorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2533),-   N-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2535),-   tert-butyl    (2R)-1-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]pyrrolidine-2-carboxylate    (Compound 2536),-   tert-butyl    N-[(3R)-1-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]pyrrolidin-3-yl[carbamate    (Compound 2537),-   N-[[6-(4-oxazol-5-ylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2546),-   N-[[6-[3-(3-methylpyrazol-1-yl)propylamino]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2550),-   N-[[6-(3-methoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2551),-   N-[(6-pyrrolidin-1-yl-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2561),-   N-[[6-(4-pyrrol-1-ylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2563),-   N-[[6-[4-(1-ethylpropyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2565),-   N-[[6-(3-acetylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2569),-   N-[[6-(3-chloro-4-methoxy-anilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2571),-   N-[[6-(3-methylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2572),-   N-[[6-(cyclopropylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2574),-   N-[[6-[(4-methoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2579),-   N-[[6-(5-fluoroisoindolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2580),-   N-[[6-[(4-chlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2585),-   N-[[6-(2-chloro-5-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2591),-   N-[[6-(chroman-3-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2595),-   N-[[6-(2-furylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2597),-   N-[[6-(5-chloro-2-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2598),-   N-[[6-[(3-pyrrol-1-ylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2600),-   N-[[6-(4-cyclohexylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2601),-   N-[[6-(2-propoxyethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2602),-   N-[[6-(2-methylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2609),-   N-[[6-[(4-ethynylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2610),-   N-[[6-(2-naphthyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2611),-   N-[(6-ethoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2617),-   N-[[6-[[4-(trifluoromethyl)phenyl]methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2618),-   N-[(6-benzyloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2619),-   N-[[6-(4-butyl-1,4-diazepan-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2620),-   N-[(6-(4-pyrimidin-2-ylpiperazin-1-yl)-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2621),-   N-[[642-(2-fluorophenyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2625),-   N-[[6-(4H-1,3-benzodioxin-2-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2627),-   N-[[6-(2-cyclopentylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2630),-   N-[[6-[2-(2-chlorophenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2632),-   N-[[6-(2-methoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2637),-   N-[(6-anilino-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2639),-   N-[[6-[(2,3-difluorophenyl)methylamino]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2640),-   N-[[6-[4-(trifluoromethyl)-1-piperidyl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2641),-   N-[[6-[2-(4-ethoxyphenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2642),-   N-[[6-[(2-methyl-8-quinolyl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2643),-   N-[[6-[(5-chloro-2-methoxy-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2645),-   N-[[6-(3-methylbut-2-enoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2648),-   N-[[6-(2,4,6-trifluorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2654),-   N-[[6-[(5-chloro-2-pyridyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2656),-   N-[[6-(2-cyanoanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2659),-   N-[[6-[(5-chloro-2-pyridyl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2747),-   N-[[6-[2-(4-pyridyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2746),-   N-[[6-(2-aminoethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2754),-   N-[(6-but-2-ynoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2753),-   N-[[6-[3-methoxypropyhmethyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2745),-   N-[[6-(4-methoxy-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2743),-   N-[[6-(1-oxoindan-5-yl)oxy-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2744),-   N-[[6-[(6-methyl-2-pyridyl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2742),-   N-[[6-(4-acetylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2741),-   N-[[6-[(2-methyl-1,3-benzothiazol-5-yl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2740),-   N-[[6-[[(1R)-1,2,2-trimethylpropyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2757),-   methyl    4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]oxy]benzoate    (Compound 2739),-   N-[[6-(2,1,3-benzoxadiazol-5-yloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2738),-   N-[[6-(4-tert-butoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2751),-   N-[[6-[isobutyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2758),-   N-[[6-(diethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2737),-   N-[[6-(3-cyanophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2736),-   N-[[6-[isopropyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2735),-   tert-butyl    N-[4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]phenyl]carbamate    (Compound 2755),-   N-[[6-[2-(3-fluorophenyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2752),-   N-[[6-[2-(1-piperidyl)phenoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2750),-   N-[[6-(2-methyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2759),-   N-[[6-[cyclopropylmethyl(propyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2734),-   N-[[6-[(2,5-dimethoxyphenyl)methylamino]-2-pyridylisulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2733),-   N-[(6-phenethyloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2732),-   N-[[6-(2,3-dichlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2731),-   N-[[6-(3-chloro-5-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2730),-   N-[[6-[(2-chlorophenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2756),-   N-[(6-chroman-4-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2749),-   N-[[6-[3-(trifluoromethyl)phenoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2729),-   N-[[6-[(2-chloro-6-fluoro-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2728),-   6-tert-butyl-N-[(6-isopentyloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2727),-   N-[[6-(1,3-benzodioxol-5-ylmethoxy)-2-pyridyl]sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2725),-   N-[[6-[(E)-but-2-enoxy]-2-pyridyl]sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2726),-   6-tert-butyl-N-[[6-[(4-methoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2723),-   N-[[6-[(3,4-dimethoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2662), and-   N-[[6-(3,5-dichlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2663)

PREPARATION 107:N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-phenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2445) Step 1: 2-Methoxypyridine-3-sulfonamide

2-Chloropyridine-3-sulfonyl chloride (5.00 g, 23.6 mmol) was dissolvedin ammonia in methanol (16.8 mL of 7 M, 117.9 mmol) and the reactionmixture was stirred for 30 minutes. The reaction mixture wasconcentrated under reduced pressure and dissolved in sodium methoxide(24.9 mL of 25%w/v, 115.1 mmol) and heated to 60° C. over 2 days. Thereaction mixture was evaporated and the residue was partitioned betweenethyl acetate and 1N HCl. The organics were separated, washed withbrine, dried over sodium sulfate and concentrated under reducedpressure. The crude material was purified by silica gel columnchromatography eluting with 0-100% ethyl acetate in hexanes to give2-methoxypyridine-3-sulfonamide (3.12 g, 70%) ESI-MS m/z calc.188.02556, found 189.0 (M₊1)⁺; Retention time: 0.23 minutes

Step 2:2,6-dichloro-N-[(2-methoxy-3-pyridyl)sulfonyl]pyridine-3-carboxamide

A mixture of 2,6-dichloropyridine-3-carboxylic acid (2.00 g, 10.4 mmol),thionyl chloride (7.45 g, 4.56 mL, 62.5 mmol), and DMF (0.1 mL) wasstirred at 45° C. for 5 hours. The reaction was concentrated underreduced pressure, dissolved in dichloromethane (5.30 mL) and slowlyadded to a solution of 2-methoxypyridine-3-sulfonamide (1.96 g, 10.4mmol) and triethylamine (3.16 g, 4.36 mL, 31.3 mmol) in dichloromethane(5.30 mL) cooled in an ice bath. The reaction mixture was stirredovernight, then diluted with dichloromethane and washed with 1 M HCl (20mL×1), water (20 mL), dried over sodium sulfate, and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (0-5% methanol in dichloromethane). The resulting solidwas dissolved in dichloromethane and washed with sodium bicarbonate ( pH5), the organic layers were dried over sodium sulfate and evaporatedunder reduced pressure to give2,6-dichloro-N-[(2-methoxy-3-pyridyl)sulfonyl]pyridine-3-carboxamide(3.50 g, 93%) ESI-MS m/z calc. 360.9691, found 362.0 (M+1)⁺; Retentiontime: 0.46 minutes.

Step 3:2,6-dichloro-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide

A mixture of2,6-dichloro-N-[(2-methoxy-3-pyridyl)sulfonyl]pyridine-3-carboxamide(0.76 g, 2.10 mmol) and HCl (5.25 mL of 4 M in dioxane, 21.0 mmol) indioxane (5 mL) was stirred at 90° C. for 90 minutes. The solvent wasevaporated under reduced pressure to give2,6-dichloro-N-((2-oxo-1,2-dihydropyridin-3-yl)sulfonyl)nicotinamide(0.72 g, 99%) as a tan solid.

Step 4:6-chloro-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

To2,6-dichloro-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide(HCl salt) (4.04 g, 10.5 mmol), (4S)-2,2,4-trimethylpyrrolidine (HClsalt) (2.36 g, 15.8 mmol), and K₂CO₃ (7.26 g, 52.5 mmol) was added DMSO(8.86 mL) and the reaction mixture was heated at 120° C. for 24 h. Thereaction mixture was diluted with ethyl acetate and the residualpotassium carbonate was filtered. The organics were washed with 0.1 Maqueous HCl (150 mL). The pH of aqueous layer was brought to 5 by theaddition of aqueous HCl, and then washed with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure to give6-chloro-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(4.15 g, 94%).

Step 5:N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-phenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2445)

6-chloro-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(30.0 mg, 0.07 mmol), phenylboronic acid (10.3 mg, 0.08 mmol),[1,3-bis(2,6-diisopropylphenyl)-2H-imidazol-2-yl]-dichloro-(3-chloro-1-pyridyl)palladium(4.80 mg, 0.01 mmol), and 2M K₂CO₃ (177 uL, 0.35 mmol) were combined inDMF (1.0 mL) and heated at 120° C. for 16 h. The reaction mixture wasfiltered and purified by LC/MS utilizing a gradient of 10-99%acetonitrile in 5 mM aq HCl to yieldN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-phenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2445). ESI-MS m/z 467.4 (M+1)⁺; Retention time: 1.13 minutes;1H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 12.53 (d, J=6.3 Hz, 1H), 8.24(dd, J=7.2, 2.2 Hz, 1H), 8.08-8.02 (m, 2H), 7.83 (dt, J=6.6, 3.3 Hz,1H), 7.76 (d, J=8.0 Hz, 1H), 7.54-7.46 (m, 2H), 7.46-7.40 (m, 1H), 7.19(d, J=8.0 Hz, 1H), 6.45 (t, J=6.8 Hz, 1H), 2.82-2.63 (m, 2H), 2.30-2.18(m , 1H), 1.89 (dd, J=11.8, 5.5 Hz, 1H), 1.62 (s, 6H), 1.45 (t, J=12.1Hz, 1H), 0.91 (d, J=6.3 Hz, 3H).

The following compounds can be synthesized using the proceduresdescribed herein:

-   6-(m-tolye-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2424),    6-(2-hydroxyphenye-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2480),    N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[4-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1799),    N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(p-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-Apyridine-3-carboxamide    (Compound 2438),-   6-(3-methoxyphenye-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1927),    N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[2-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2514),-   6-[3-(hydroxymethyl)phenyl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1997),-   6-(4-methoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2080),-   N-(benzenesulfonyl)-6-(6-methoxy-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2411),-   6-(3-fluoro-5-isobutoxy-phenye-N-(3-hydroxyphenyl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1885),-   N-(benzenesulfonyl)-6-(2-hydroxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2133),-   6-(3-fluoro-5-isobutoxy-phenye-N-(4-hydroxyphenyl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1750),-   6-(3-fluoro-5-isobutoxy-phenye-N-(2-hydroxyphenyl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1836),-   6-(3-fluoro-5-isobutoxy-phenye-N-(4-methoxyphenyl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1876),-   N-(benzenesulfonyl)-6-phenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2092),-   N-(benzenesulfonyl)-2-[(3S)-2,2-dideuterio-3,5,5-trimethyl-pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2560),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-ethoxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1860),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1740),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1H-indol-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2125),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(dimethylamino)pyrimidin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2021),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1H-indol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2478),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-hydroxy-3,5-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1923),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2416),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxy-6-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2103),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxy-5-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2071),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2363),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1-methylindol-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2352),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1,3,5-trimethylpyrazol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2668),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2,5-difluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2388),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-hydroxy-2-naphthyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2468),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-hydroxy-3-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2614),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2086),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-pyridylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2377),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(2-pyridylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1832),-   6-(3,5-dimethylphenyl)-N-[(6-isopentyloxy-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2707) and-   2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamide    (Compound 307).

PREPARATION 108:N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191) Step 1: 1-(3-hydroxypyrazol-1-yl)ethanone

1H-pyrazol-5-ol (1.02 g, 12.1 mmol) and pyridine (5.0 mL, 61.8 mmol)were stirred at 95° C. and a solution of acetic anhydride (1.24 g, 1.14mL, 12.1 mmol) in pyridine (2.0 mL, 24.7 mmol) was added dropwise over aperiod of 3 minutes. The reaction mixture was then stirred at 95° C. foran additional 1.5 h. The solvents were removed under reduced pressureand the solid residue was triturated with diethylether (30 mL),filtered, washed with diethylether and dried under high vacuum to give1-(3-hydroxypyrazol-1-yl)ethanone (1.34 g, 88%) as a yellow solid.ESI-MS m/z calc. 126.04293, found 127.1 (M+1)⁺; Retention time: 0.3minutes; 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.12 (d, J=2.9 Hz,1H), 6.00 (d, J=3.0 Hz, 1H), 2.48 (s, 3H).

Step 2: 1-(3-isobutoxypyrazol-1-yl)ethanone

To 1-(3-hydroxypyrazol-1-yl)ethanone (1.25 g, 9.91 mmol), potassiumcarbonate (2.06 g, 14.9 mmol) and anhydrous DMF (10 mL) under nitrogenatmosphere was added 1-bromo-2-methyl-propane (1.49 g, 1.19 mL, 10.9mmol). The reaction was stirred at 80° C. for 2 hours. The reactionmixture was diluted with EtOAc (50 ml) and water (25 mL) and two phaseswere separated. The aqueous phase (pH=9-10) was further extracted withEtOAc (20 mL). The combined extracts were dried over sodium sulfate andthe solvents evaporated. The resulting oil was purified by silica gelcolumn chromatography using a gradient of EtOAc (0 to 30%) in hexanes togive 1-(3-isobutoxypyrazol-1-yl)ethanone (1.24 g, 69%) as a colorlessoil. ESI-MS m/z calc. 182.10553, found 183.3 (M+1)⁺; Retention time:1.35 minutes; 1H NMR (400 MHz, Chloroform-d) δ 8.05 (d, J=3.0 Hz, 1H),5.96 (d, J=3.0 Hz, 1H), 3.99 (d, J=6.6 Hz, 2H), 2.58 (s, 3H), 2.08 (dq,J=12.9, 6.4 Hz, 1H), 1.01 (d, J=6.7 Hz, 6H).

Step 3: 3-isobutoxy-1H-pyrazole

1-(3-isobutoxypyrazol-1-yl)ethanone (1.24 g, 6.82 mmol) was treated withMeOH (20 mL) and NaOH (1.14 mL of 6 M, 6.82 mmol) (6N aqueous) at roomtemperature for 2 hours. The volatiles were removed under reducedpressure. The residue was taken in EtOAc (25 mL) and brine (20 ml) andtwo phases were separated. The aqueous phase was further extracted withEtOAc (2×25 mL) and the combined extracts were dried over sodium sulfateand concentrated under reduced pressure to give 3-isobutoxy-1H-pyrazole(955 mg, 99%) as a slightly colored viscous oil. ESI-MS m/z calc.140.09496, found 141.2 (M₊1)⁺; Retention time: 0.86 minutes; 1H NMR (400MHz, Chloroform-d) δ 9.25 (very broad s, 1H), 7.35 (d, J=2.5 Hz, 1H),5.73 (d, J=2.5 Hz, 1H), 3.91 (d, J=6.7 Hz, 2H), 2.15-2.02 (m, 1H),1.06-0.98 (m, 6H).

Step 4: tert-butyl2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylate

NaH (64 mg, 1.6 mmol) (60% oil suspension) was added to3-isobutoxy-1H-pyrazole (224 mg, 1.60 mmol) in anhydrous DMF (2 mL). Thereaction mixture was stirred until gas evolution stopped. Tert-butyl2,6-dichloropyridine-3-carboxylate (330 mg, 1.33 mmol) was added and thereaction mixture was stirred at 100° C. under nitrogen for 30 minutes.The reaction mixture was diluted with EtOAc (50 mL) and water +brine (40mL) and the two phases were separated. The aqueous phase was furtherextracted with EtOAc (2×30 mL). The combined extracts were dried oversodium sulfate and the solvent removed under reduced pressure to give aresidue, which was purified by silica gel column chromatography using agradient of AcOEt (0 to 20%) in hexanes to give tert-butyl2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylate (235 mg, 50%)as an off-white solid). ESI-MS m/z calc. 351.13498, found 352.2(M+1)^(±); Retention time: 2.34 minutes, 1H NMR (400 MHz, Chloroform-d)δ 8.35 (d, J=2.8 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz,1H), 5.97 (d, J=2.9 Hz, 1H), 4.02 (d, J=6.6 Hz, 2H), 2.12 (dp, J=13.4,6.7 Hz, 1H), 1.62 (s, 9H), 1.03 (d, J=6.7 Hz, 6H).

Step 5: 2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylic acid

Tert-butyl 2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylate(203 mg, 0.57 mmol), DCM (2 mL) and TFA (615 4, 7.98 mmol) were stirredat 40-45° C. for 3 hours. The volatiles were remove under reducedpressure to give2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylic acid (170 mg,100%) as a white solid. ESI-MS m/z calc. 295.07236, found 296.3 (M+1)⁺;Retention time: 1.64 minutes; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H),8.41 (d, J=2.9 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H),6.20 (d, J=2.9 Hz, 1H), 4.02 (d, J=6.6 Hz, 2H), 2.06 (hept, J=6.6 Hz,1H), 0.98 (d, J=6.7 Hz, 6H).

Step 6:N-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxamide

DMF (1.2 mL) was added to2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxylic acid (128 mg,0.43 mmol) and CDI (87 mg, 0.54 mmol) under an atmosphere of nitrogen.The reaction mixture was stirred at 40° C. under nitrogen for 1 hour.2-aminopyridine-3-sulfonamide (91 mg, 0.53 mmol) was dissolved undernitrogen in anhydrous DMF (1.2 mL) and NaH (21 mg, 0.53 mmol) (60% oilsuspension) was added and the reaction mixture was stirred undernitrogen until gas evolution stopped and then stirred at 40° C. for 45minutes. The two reaction mixtures were combined and stirred at roomtemperature for 1.5 hours. Water and ice was added, followed by aceticacid (400 μL, 7.03 mmol). The resulting solid was filtered, washed withwater and dried to giveN-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxamide(189 mg, 97%) as a white solid. ESI-MS m/z calc. 450.0877, found 451.4(M+1)+; Retention time: 1.42 minutes.

Step 7:N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191)

N-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxamide(177 mg, 0.39 mmol), (4S)-2,2,4-trimethylpyrrolidine (HCl salt) (237 mg,1.58 mmol), K₂CO₃ (327 mg, 2.37 mmol) and anhydrous DMSO (550 μL) wereheated at 150° C. for 6 hours under an atmosphere of nitrogen. Thereaction mixture was then cooled and a stirred mixture of water (40 mL)and acetic acid (400 μL, 7.034 mmol) was added dropwise. The resultingyellow solid was filtered and washed with water. The solid was dissolvedin dichloromethane and the organic phase was dried over sodium sulfateand concentrated under reduced pressure. The resulting solid waspurified by silica gel column chromatography using a gradient of MeOH (0to 10%) in DCM, followed by purification by reverse phase preparativeHPLC using a gradient of MeCN in water (1 to 99% over 15 min) and HCl asa modifier to giveN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2191) (77 mg, 36%) as a pale yellow solid. ESI-MS m/z calc.527.23145, found 528.3 (M+1)⁺; Retention time: 1.55 minutes; 1H NMR (400MHz, DMSO-d6) δ 12.45 (broad s, 1H), 8.28-8.22 (m, 1H), 8.20 (d, J=2.7Hz, 1H), 8.06-7.99 (m, 1H), 7.84 (d, J=8.3 Hz, 1H), 6.94 (d, J=8.3 Hz,1H), 6.77 (dd, J=7.7, 4.9 Hz, 1H), 6.69 (br s, 2H), 6.12 (d, J=2.6 Hz,1H), 3.98 (d, J=6.6 Hz, 2H), 2.45 (d, J=8.6 Hz, 2H), 2.13-2.01 (m , 2H),1.90-1.79 (m, 1H), 1.55 (s, 3H), 1.53 (s, 3H), 1.38 (t, J=12.1 Hz, 1H),0.98 (d, J=6.8 Hz, 6H), 0.74 (d, J=6.2 Hz, 3H).

PREPARATION 109:N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975) Step 1: 143-(2,2-dimethylpropoxy)pyrazol-1-yl]ethanone

To a suspension of 1-(3-hydroxypyrazol-1-yl)ethanone (1.21 g, 9.60 mmol)in anhydrous THF (20 mL) was added triphenyl phosphine (2.78 g, 10.6mmol) and 2,2-dimethylpropan-1-ol (846 mg, 9.60 mmol). The reactionmixture was cooled down in an ice-bath under nitrogen. DIAD (2.1 mL,10.7 mmol) was added dropwise via a syringe over 3 min. The reactionmixture was then stirred under nitrogen warming to room temperatureovernight. The reaction mixture was diluted with ethyl acetate (100 mL)and the combined organic phase was washed with aqueous saturated sodiumbicarbonate (2×50 mL), brine (50 mL) and dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography using a gradient of ethyl acetate (0 to 30%)in hexanes. to provide 1-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]ethanone(967 mg, 51%) as a yellow solid. ESI-MS m/z calc. 196.12119, found 197.3(M+1)⁺; Retention time: 1.62 minutes; 1H NMR (400 MHz, Chloroform-d) δ8.05 (d, J=3.0 Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 3.89 (s, 2H), 2.58 (s,3H), 1.03 (s, 9H).

Step 2: 3-(2,2-dimethylpropoxy)-1H-pyrazole

1-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]ethanone (960 mg, 4.89 mmol),MeOH (15 mL) and NaOH (815 μL of 6 M, 4.89 mmol) (6N aqueous) werestirred at room temperature for 21 hours. The volatiles were removedunder reduced pressure. The residue was taken in EtOAc (25 mL) and brine(20 ml) and two phases were separated. The aqueous phase was furtherextracted with EtOAc (2×25 mL) and the combined organic extracts weredried over sodium sulfate and evaporated under reduced pressure to give3-(2,2-dimethylpropoxy)-1H-pyrazole (719 mg, 95%) as an off-white solid.ESI-MS m/z calc. 154.11061, found 155.3 (M+H)⁺; Retention time: 1.13minutes; 1H NMR (400 MHz, Chloroform-d) δ 7.36 (d, J=2.4 Hz, 1H), 5.74(d, J=2.5 Hz, 1H), 3.81 (s, 2H), 1.02 (s, 9H).

Step 3: Tert-butyl2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylate

NaH (95 mg, 2.375 mmol) (60% oil suspension) (slight exotherm noticed)was added'to 3-(2,2-dimethylpropoxy)-1H-pyrazole (363 mg, 2.35 mmol) inanhydrous DMF (3 mL) and the reaction mixture was stirred until gasevolution stopped. Tert-butyl 2,6-dichloropyridine-3-carboxylate (530mg, 2.14 mmol) was added portionwise and the reaction mixture wasstirred at 100° C. under nitrogen for 1 hour. The reaction mixture wasdiluted with EtOAc (60 mL) and water +brine (60 mL) and the two phaseswere separated. The aqueous phase was further extracted with EtOAc (2×30mL). The combined extracts were dried over sodium sulfate and thesolvent removed under reduced pressure. The residue was purified bysilica gel column chromatography using a gradient of EtOAc (0 to 20%over 40 min) in hexanes to give tert-butyl2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylate(497 mg, 64%) as a yellow solid. ESI-MS m/z calc. 365.1506, found 366.2(M₊1)⁺; Retention time: 2.44 minutes.

Step 4:2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylicacid

Tert-butyl2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylate(497 mg, 1.36 mmol), DCM (5 mL) and TFA (1.5 mL, 19.5 mmol) were stirredat 40° C. for 4 hours. The volatiles were removed by evaporation underreduced pressure to give2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylicacid (413 mg, 98%) as a white solid. ESI-MS m/z calc. 309.088, found310.1 (M+1)⁺; Retention time: 1.8 minutes; 1H NMR (400 MHz, DMSO-d6) δ13.58 (s, 1H), 8.42 (dd, J=2.8, 0.8 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H),7.74 (d, J=8.5 Hz, 1H), 6.22 (dd, J=2.8, 0.8 Hz, 1H), 3.93 (s, 2H), 1.01(s, 9H).

Step 5:N-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxamide

DMF (1 mL) was added to2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylicacid (105 mg, 0.34 mmol) and CDI (69 mg, 0.43 mmol) and the reactionmixture was stirred at 40° C. under nitrogen for 1 hour. In a separate 4mL vial, 2-aminopyridine-3-sulfonamide (73 mg, 0.42mmo1) was dissolvedunder nitrogen in anhydrous DMF (1 mL). NaH (22 mg, 0.55 mmol) (60% oilsuspension) was added and the reaction mixture was stirred undernitrogen until gas evolution stopped, then stirred at 40° C. for onehour. The two reaction mixtures were combined and stirred at roomtemperature for 4 hours. Water and ice was added, followed by aceticacid (400 μL, 7.034 mmol). The resulting solid was filtered, washed withwater and dried to giveN-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxamide(150 mg, 95%) as a white solid. The product was used for the next stepwithout any further purification. ESI-MS m/z calc. 464.10336, found465.2 (M+1)⁺; Retention time: 1.5 minutes.

Step 6:N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975)

N-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxamide(150 mg, 0.32 mmol), (4S)-2,2,4-trimethylpyrrolidine (HCl salt) (195 mg,1.30 mmol), K₂CO₃ (274 mg, 1.98 mmol) and anhydrous DMSO (480 μL) werestirred at 150° C. for 7.5 hours under an atmosphere of nitrogen. Thereaction mixture was poured into a mixture of water (25 mL) and aceticacid (400 μL, 7.034 mmol)and the resulting yellow solid was separated byfiltration. The wet solid was dissolved in DCM, the organic phase wasdried over sodium sulfate and the solvents evaporated to give a crudeglass, which was purified by silica gel column chromatography using agradient of MeOH (0 to 10%) in DCM. Evaporation of the solvent gave anoff-white solid which was dissolved in MeOH (3 mL) and purified byreverse phase preparative HPLC using a gradient of MeCN in water (1 to99% over 15 min) and HCl as a modifier (3×950 uL injections) to giveN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1975) (75 mg, 42%) as a tan solid. ESI-MS m/z calc. 541.24713,found 542.3 (M+1)⁺; Retention time: 1.65 minutes; 1H NMR (400 MHz,DMSO-d6) δ 12.45 (s, 1H), 8.24 (dd, J=4.7, 1.9 Hz, 1H), 8.20 (d, J=2.8Hz, 1H), 8.03 (dd, J=7.8, 1.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 6.95 (d,J=8.2 Hz, 1H), 6.77 (dd, J=7.8, 4.8 Hz, 1H), 6.69 (broad s, 2H), 6.14(d, J=2.7 Hz, 1H), 3.89 (s, 2H), 2.45 (d, J=8.9 Hz, 2H), 2.12 (br s,1H), 1.85 (dd, J=11.9, 5.4 Hz, 1H), 1.55 (s, 3H), 1.53 (s, 3H),1.43-1.33 (m, 1H), 1.00 (s, 9H), 0.74 (d, J=6.2 Hz, 3H).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2036),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2406),-   6-(3-isopropoxypyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2360),-   N-(benzenesulfonyl)-6-(4-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1912),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-4-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2248),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2-ethoxyethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1742),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2603),-   6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2578),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(4-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1895),-   6-(3-isobutoxy-4-methyl-pyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1743),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isopropoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1844),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[(2S)-2-methylbutoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2458),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-sec-butoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1970),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(3-hydroxy-2-methyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2192),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isopropoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1709),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxy-4-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1758),-   N-cyclopropylsulfonyl-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2554),-   6-(4-isobutoxypyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1760),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxy-5-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2238),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[2-(2-ethoxyethoxy)ethoxylpyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2326),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamide    (Compound 2604) (Isomer 1) (Compound 2481) (Isomer 2)    (Compound 2194) (Isomer 3) (Compound 2615) (Isomer 4),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1887),-   6-(3-ethoxy-4-methyl-pyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1856),-   6-(3-isobutoxypyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1896),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1952),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[3,3,3-trideuterio-2,2-bis(trideuteriomethyl)propoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2703),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(1-methylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2704),-   N-(benzenesulfonyl)-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1114),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-cyclopropylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2701),-   N-cyclopropylsulfonyl-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-phenylpyrazol-1-yl)pyridine-3-carboxamide    (Compound 2676),-   N-cyclopropylsulfonyl-6-(3-phenylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2674),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-phenylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2702),-   N-[(2-amino-3-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxamide    (Compound 1732),-   N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2716),-   N-cyclopropylsulfonyl-6-[3-(2-pyridyl)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2718),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)-4-methyl-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2699),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(cyclobutylmethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2694) and-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(cyclopropylmethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2695).

PREPARATION 110:N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamide(Compound 2604) (Isomer 1, R or S stereoisomer) andN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamide(Compound 2481) (Isomer 2, R or S stereoisomer)

The stereoisomers were separated using supercritical fluidchromatography on a ChiralPak AD-H (250×10 mm), 5 μm column using 30%methanol in CO₂ at a flow rate of 10.0 mL/min. The separated enantiomerswere separately concentrated, diluted with ethyl acetate (3 mL) andwashed with IN aqueous hydrochloric acid. The organic layers were driedover sodium sulfate, filtered, and evaporated to dryness to give thepure compounds. SFC Peak 1:N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamide(Compound 2604) (Compound 2481) ESI-MS m/z calc. 539.23145, found 540.2(M+1)⁺; Retention time: 1.67 minutes . SFC Peak 2:N-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamide(Compound 2604) (Isomer 1, R or S stereoisomer) (Compound 2481) (Isomer2, R or S stereoisomer) ESI-MS m/z calc. 539.23145, found 540.2 (M+1) ;Retention time: 1.67 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[6-methyl-8-azaspiro[3.4]octan-8-yl]pyridine-3-carboxamide    (Compound 2358) (Isomer 1, R or S stereoisomer), followed by SFC    column chromatography using ChiralPak AS-H (250×10 mm), 5 μm, using    as eluent 38% MeOH (no modifier) in CO₂,-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[(1-methylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2594) (Isomer 2, R or S stereoisomer) using ChiralPak IA    (250×4.6 mm), 5 μm; Mobile phase: 25% MeOH:EtOH (50:50; 0.1% TFA) in    CO_(2.)

PREPARATION 111: 4-(2,2-dimethylpropoxy)-1H-pyrazole Step 1: tert-butyl4-hydroxypyrazole-1-carboxylate

To tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate(25 g, 85 mmol) in THF (170 mL) at 0° C. was added sodium hydroxide (85mL of 2 M, 170 mmol) followed by hydrogen peroxide (19.27 mL of 30% w/v,170.0 mmol) and the reaction mixture was stirred at 0° C. for 10 min andRT for 45 min. The reaction mixture was cooled to 0° C. and diluted withDCM and 2 M HCl was added till pH 2 was reached. The organics wereseparated, dried and concentrated under reduced pressure to givetert-butyl 4-hydroxypyrazole-1-carboxylate (15 g 100%) as yellow solid.ESI-MS m/z calc 184.19 , found 185.0 (M+1)⁺; LCMS retention time (3 minrun) 0.63 min.

Step 2: 4-(2,2-dimethylpropoxy)-1H-pyrazole

To tert-butyl 4-hydroxypyrazole-1-carboxylate (1000 mg, 5.429 mmol) andPh₃P (2.136 g, 8.144 mmol) in THF (2.500 mL) was added2,2-dimethylpropan-1-ol (717.9 mg, 8.144 mmol) at 0° C. To the reactionmixture was added DIAD (1.647 g, 1.578 mL, 8.144 mmol) in THF (2 mL).The reaction mixture was stirred at 60° C. for 16 h, then cooled anddiluted with DCM and washed with 6 M HCl solution. The organics wereseparated, dried and concentrated to give a residue which was purifiedby silica gel column chromatography using 5-100% EA-hexanes followed by5-40% EA-DCM to give tert-butyl4-(2,2-dimethylpropoxy)pyrazole-1-carboxylate (435.5 mg) ESI-MS m/z calc254.16, found 255.4 (M₊1)⁺; LCMS retention time (3 min run)=1.82 min; 1HNMR (400 MHz, Chloroform-d) δ 7.57 (d, J=1.0 Hz, 1H), 7.51 (d, J=1.0 Hz,1H), 3.52 (s, 2H), 1.64 (s, 9H), 1.00 (s, 9H). To tert-butyl4-(2,2-dimethylpropoxy)pyrazole-1-carboxylate (435.5 mg, 1.712 mmol) inDCM (0.2 mL) was added 4M HCl-dixoane (2 mL). After 5 h at RT, thesolvent was removed under reduced pressure and the residue wastriturated with diethyl ether to give4-(2,2-dimethylpropoxy)-1H-pyrazole (HCl salt) (210 mg, 20%) ESI-MS m/zcalc 154.11 , found 155.4 (M₊1)⁺; LCMS retention time(3 min run) 1.13min.

PREPARATION 112: 3-isobutoxy-4-methyl-1H-pyrazole Step 1:1-(3-hydroxy-4-methyl-pyrazol-1-yl)ethanone

4-methyl-1H-pyrazol-3-ol (1.0 g, 10.2 mmol) and pyridine (4.0 mL, 49.5mmol) were heated at 95° C. A solution of acetic anhydride (1.0 g, 961.2μL, 10.2 mmol) in pyridine (1.5 mL, 18.6 mmol) was added dropwise over aperiod of 2 minutes. The reaction mixture was then stirred at 95° C. foran additional 2 hours. The solvents were removed under reduced pressureand the solid residue was triturated with diethylether (30 mL),filtered, washed with diethylether and dried to give1-(3-hydroxy-4-methyl-pyrazol-1-yl)ethanone (1.2 g, 86%) as a whitesolid. ESI-MS m/z calc. 140.05858, found 141.1 (M+1)⁺; Retention time0.39 minutes; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.92 (q, J=1.1Hz, 1H), 2.43 (s, 3H), 1.88 (d, J=1.2 Hz, 3H).

Step 2: 1-(3-isobutoxy-4-methyl-pyrazol-1-yl)ethanone

1-Bromo-2-methyl-propane (658 mg, 522 μL, 4.80 mmol) was added to1-(3-hydroxy-4-methyl-pyrazol-1-yl)ethanone (612 mg, 4.37 mmol),potassium carbonate (905 mg, 6.55 mmol) and anhydrous DMF (5 mL) undernitrogen atmosphere. The reaction mixture was stirred at 80° C. for 2.5hours, then diluted with EtOAc (50 ml) and water (25 mL) and two phaseswere separated. The aqueous phase (pH=9-10) was further extracted withEtOAc (20 mL). The combined extracts were dried over sodium sulfate andthe solvents evaporated to give a crude oil. The oil was purified bysilica gel column chromatography using a gradient of AcOEt (0 to 30%) inhexanes to provide 1-(3-isobutoxy-4-methyl-pyrazol-1-yl)ethanone (726mg, 85%) as a colorless liquid. ESI-MS m/z calc. 196.12119, found 197.3(M+1)⁺; Retention time: 1.57 minutes; 1H NMR (400 MHz, Chloroform-d) 67.82 (s, 1H), 4.01 (d, J=6.6 Hz, 2H), 2.53 (s, 3H), 2.10 (sep, J=6.7 Hz,1H), 1.95 (d, J=1.0 Hz, 3H), 1.01 (d, J=6.7 Hz, 6H).

Step 3: 3-isobutoxy-4-methyl-1H-pyrazole

1-(3-isobutoxy-4-methyl-pyrazol-1-yl)ethanone (726 mg, 3.70 mmol) wastreated with MeOH (10 mL) and NaOH (617 μL of 6 M, 3.70 mmol) (6Naqueous) at room temperature for 2 hours. The volatiles were removedunder reduced pressure. The residue was taken in EtOAc (25 mL) and brine(20 ml) and two phases were separated. The aqueous phase was furtherextracted with EtOAc (2×25 mL) and the combined extracts were dried oversodium sulfate. After evaporation of the solvent,3-isobutoxy-4-methyl-1H-pyrazole (564 mg, 99%) was isolated as aslightly colored viscous oil. ESI-MS m/z calc. 154.11061, found 155.0(M₊1)⁺; Retention time: 1.17 minutes; 1H NMR (400 MHz, Chloroform-d) δ8.83 (broad s, 1H), 7.16-7.09 (m, 1H), 3.95 (d, J=6.7 Hz, 2H), 2.09 (m,1H), 1.95 (d, J=0.9 Hz, 3H), 1.01 (d, J=6.7 Hz, 6H).

The following compounds can be prepared following the proceduresdescribed herein:

3-(2-ethoxyethoxy)-1H-pyrazole,

(S)-3-(2-methylbutoxy)-1H-pyrazole,

3-(sec-butoxy)-1H-pyrazole,

3-((1H-pyrazol-5-yl)oxy)-2-methylpropan-1-ol,

5-isopropoxy-1H-pyrazole,

5-isobutoxy-3-methyl-1H-pyrazole,

3-(2-(2-ethoxyethoxy)ethoxy)-1H-pyrazole and

3-(2-(methyl-d3)propoxy-2,3,3,3-d4)-1H-pyrazole

PREPARATION 113:N-[(6-amino-2-pyridyl)sulfonyl]-3-fluoro-4-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]benzamide(Compound 2634) Step 1:N-[(6-amino-2-pyridyl)sulfonyl]-4-bromo-2,3-difluoro-benzamide

To 4-bromo-2,3-difluoro-benzoic acid (2.66 g, 11.2 mmol) in DMF (2.30mL) was added at RT di(imidazol-1-yl)methanone (2.73 g, 16.8 mmol) andreaction mixture was heated at 65° C. for 1 h. Separately to6-aminopyridine-2-sulfonamide (2.43 g, 14.0 mmol) in DMF (2 mL) wasadded sodium hydride (561 mg, 14.0 mmol) at 0° C. and stirred for 10 minand RT for 1 h. The reaction mixture was cooled back to 0° C. and theCDI adduct was added and reaction mixture was heated at 65° C. for 1.5h, then cooled to RT and diluted with ethyl acetate and washed withbrine solution. The organics were separated, dried and concentratedunder reduced pressure to give a residue which was purified by silicagel column chromatography eluting with 0-100% ethyl acetate-hexanes togive N-[(6-amino-2-pyridyl)sulfonyl]-4-bromo-2,3-difluoro-benzamide(3.80 g, 986%). ESI-MS m/z calc 390.94, found 394.2 (M+4)⁺; LCMSretention time (3 min run) 1.13 min.

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-2,3-difluoro-4-(3-fluoro-5-isobutoxy-phenyl)benzamide

To mixture ofN-[(6-amino-2-pyridyl)sulfonyl]-4-bromo-2,3-difluoro-benzamide (1.3 g,3.3 mmol) and (3-fluoro-5-isobutoxy-phenyl)boronic acid (1.1 g, 5.0mmol) and K₂CO₃ (1.4 g, 9.9 mmol) was addedcyclopentyl(diphenyl)phosphane;dichloropalladium;iron (243 mg, 0.33mmol) and DMF (8.8 mL) and water (2.2 mL) and the reaction mixture wasstirred under nitrogen at 100° C. for 16 h. The reaction mixture wascooled, filtered over pad of Celite and filtrate was diluted with ethylacetate and brine solution. The organics were separated, dried andconcentrated to give a residue which was purified by silica gel columnchromatography using 5-100% ethyl acetate-DCM as eluent to giveN-[(6-amino-2-pyridyl)sulfonyl]-2,3-difluoro-4-(3-fluoro-5-isobutoxy-phenyl)benzamide(356 mg, 22%). 1H NMR (400 MHz, Methanol-d4) δ 7.64-7.53 (m, 2H), 7.29(d, J=7.4 Hz, 1H), 7.25-7.18 (m, 1H), 6.90 (d, J=2.7 Hz, 1H), 6.88-6.81(m, 1H), 6.73 (dt, J=10.8, 2.3 Hz, 1H), 6.64 (d, J=8.3 Hz, 1H), 3.79 (d,J=6.4 Hz, 2H), 2.07 (hept, J=6.7 Hz, 1H), 1.04 (d, J=6.7 Hz, 6H); ESI-MSm/z calc 479.11 , found 480.2 (M+1)⁺; LCMS retention time (3 min run)1.78 min.

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-3-fluoro-4-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-Abenzamide(Compound 2634)

[ToN-[(6-amino-2-pyridyl)sulfonyl]-2,3-difluoro-4-(3-fluoro-5-isobutoxy-phenyl)benzamide(356 mg, 0.74 mmol) and K₂CO₃ (277 mg, 2.00 mmol) in NMP (650 μl) wasadded (4S)-2,2,4-trimethylpyrrolidine (HCl salt) (150 mg, 1.00 mmol) andthe reaction mixture was stirred at 195° C. for 5 h, then cooled andfiltered and diluted with EtOAc and brine solution. The organics wereseparated, dried and concentrated under reduced pressure to give aresidue which was purified using silica gel column chromatography using0-15% MeOH-DCM to giveN-[(6-amino-2-pyridyl)sulfonyl]-3-fluoro-4-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]benzamide(Compound 2634) (42 mg, 2%) 1H NMR (400 MHz, Methanol-d4) δ 7.69 (s,1H), 7.32 (t, J=7.9 Hz, 1H), 7.26 (s, 1H), 7.08 (dd, J=7.3, 0.8 Hz, 1H),6.62-6.51 (m, 2H), 6.44 (dd, J=19.3, 9.7 Hz, 2H), 3.58 (s, 1H), 3.49 (d,J=6.4 Hz, 2H), 2.52 (t, J=0.8 Hz, 1H), 2.45 (s, 1H), 1.90 (s, 1H),1.82-1.69 (m, 2H), 1.53 (s, 1H), 1.04 (s, 3H), 0.92 (s, 6H), 0.74 (d,J=6.7 Hz, 6H). ESI-MS m/z calc 572.2 , found 573.3 (M+1)⁺; LCMSretention time (3 min run) 1.91 min.

PREPARATION 114:N-[(6-amino-5-hydroxy-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2331) Step 1: 6-bromo-2-nitro-pyridin-3-ol

A solution of phenyl trimethyl ammonium tribromide (8.45 g, 22.3 mmol)in THF (68 mL) was added dropwise to a stirred solution of2-nitropyridin-3-ol (3.00 g, 21.4 mmol) and triethylamine (4.33 g, 5.97mL, 42.8 mmol) in THF (91 mL) at −40° C. The addition was done over aperiod of 5 minutes and the reaction mixture was kept at −40° C. for 1h. 1N HCl and aq. Na₂S₂O₃ were added and the aq. phase was extractedwith dichloromethane. The combined organic phase was washed with brine,dried over MgSO₄, filtered and the filtrate evaporated under reducedpressure. The residue was purified by silica gel column chromatographyeluted with 30 to 100% EtOAc/Hexanes to afford the title compound as ayellow solid.

Step 2: 3-benzyloxy-6-bromo-2-nitro-pyridine

To a solution of 6-bromo-2-nitro-pyridin-3-ol (5.04 g, 23.0 mmol) in DMF(40 mL) was added potassium carbonate (6.36 g, 46.0 mmol) followed bythe addition of bromomethylbenzene (4.13 g, 2.87 mL, 24.2 mmol). Thereaction mixture was heated at 60° C. overnight, then partitionedbetween EtOAc and water. The aqueous layer was extracted with EtOAc(3×). The combined organic layers were washed with water (3×), brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude material was suspended in hexane, collected via filtration and airdried to provide 3-benzyloxy-6-bromo-2-nitro-pyridine (6.22 g, 87%) as ayellow solid.

Step 3: methyl 3[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]propanoate

A mixture of 3-benzyloxy-6-bromo-2-nitro-pyridine (6.21 g, 20.1 mmol)and (3-methoxy-3-oxo-propyl)sulfinyloxysodium (3.50 g, 20.1 mmol) inDMSO (50 mL) was purged with nitrogen for 2 minutes. Iodocopper (7.66 g,40.2 mmol) was added. The reaction mixture was heated at 80° C. for 24h, then partitioned between EtOAc and sat. NH₄Cl. The resultingprecipitate was removed via filtration and washed with EtOAc. Theaqueous layer was extracted with EtOAc (3×). The combined organic layerswere washed with water (3×), brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified bysilica gel column chromatography (40-60% EtOAc-Hex) to provide methyl3-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]propanoate (2.50 g, 33%) as abrown solid.

Step 4: 5-benzyloxy-6-nitro-pyridine-2-sulfinate

THF (1 mL) was added to a suspension of methyl3-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]propanoate (76 mg, 0.2 mmol)in MeOH (2 mL). Sodium methoxide (400 μL of 0.5 M, 0.2 mmol) (in MeOH)was added dropwise. The reaction mixture was stirred at room temperaturefor 30 minutes, then evaporated under reduced pressure to provide alight brown solid. The crude material was used directly in next stepwithout further purification.

Step 5: 5-benzyloxy-6-nitro-pyridine-2-sulfonamide

To a solution of amino hydrogen sulfate (3.68 g, 32.5 mmol) and sodiumacetate (5.32 g, 65.0 mmol) in water (40 mL) was added5-benzyloxy-6-nitro-pyridine-2-sulfinate (sodium salt) (2.06 g, 6.5mmol) in MeOH (25 mL). The reaction mixture was stirred at roomtemperature overnight, then partitioned between water and EtOAc. Theaqueous layer was extracted with EtOAc (3×). The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure to provide5-benzyloxy-6-nitro-pyridine-2-sulfonamide (1.10 g, 55%) as a crudematerial. The crude material (light yellow solid) was used directly innext step without further purification.

Step 6:N-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide

To a mixture of 5-benzyloxy-6-nitro-pyridine-2-sulfonamide (155 mg, 0.50mmol),2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylicacid (248 mg, 0.60 mmol) and HATU (228 mg, 0.60 mmol) in DMF (10 mL) wasadded potassium carbonate (207 mg, 1.50 mmol). The reaction mixture washeated at 60° C. for 7 h, partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc (3×). The combined organic layerswere washed with water (3×), brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified bysilica gel column chromatography (20-40% EtOAc-Hex) to provideN-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(220 mg, 63%) as a yellow solid.

Step 7:N-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 1762)

To a solution ofN-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(215 mg, 0.31 mmol) in dioxane (4 mL) and ethanol (2 mL) was added Fe(171 mg, 3.07 mmol) and HCl (511 μL of 6 M, 3.07 mmol). The reactionmixture was heated at 65° C. for 30 min. The iron was removed and theprecipitate was collected via filtration. The filtrate was concentratedto dryness, dissolved in DMSO, filtered and purified by preparative HPLCto provideN-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 1762) (25 mg, 12%) 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H),8.13 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.57-7.46 (m, 2H),7.45-7.23 (m, 5H), 7.23-7.04 (m, 5H), 6.83 (dt, J=10.9, 2.3 Hz, 1H),6.33 (s, 2H), 5.24 (s, 2H), 3.61 (d, J=6.6 Hz, 2H), 2.05 (s, 6H), 1.98(dt, J=13.4, 6.7 Hz, 1H), 0.96 (d, J=6.6 Hz, 6H). ESI-MS m/z calc.670.22614, found 670.0 (M+1)⁺; Retention time: 3.6 minutes.

Step 8:N-[(6-amino-5-hydroxy-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2331)

To a suspension ofN-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 1762) (21 mg, 0.03 mmol) in MeOH (20 mL) was added EtOAc (1mL). The solution was purged with nitrogen for 2 min. Pd (3. mg, 0.003mmol) was added. The reaction mixture was stirred under an atmosphere ofhydrogen at room temperature overnight. The Pd catalyst was removed viafiltration. The filtrate was concentrated to dryness. The residue wasre-dissolved in DMSO and purified by preparative HPLC to provideN-[(6-amino-5-hydroxy-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2331) (5.0 mg, 24%). ESI-MS m/z calc. 580.1792, found 580.0(M+1)⁺; Retention time: 3.15 minutes.

PREPARATION 115:N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-fluoro-5-isobutoxy-phenyl)-4-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrimidine-5-carboxamide(Compound 2121) Step 1:2,4-dichloro-N-((6-nitropyridin-2-yl)sulfonyl)pyrimidine-5-carboxamide

A solution of 2,4-dichloropyrimidine-5-carboxylic acid (4.56 g, 23.8mmol) in thionylchloride (30 mL) was refluxed for 1 hour, and evaporatedto remove thionylchloride. The residue was dissolved in dichloromethane(50 mL), and 6-nitropyridine-2-sulfonamide (5.14 g, 23.7 mmol) wascarefully added followed by trimethylamine (10 mL). The reaction mixturewas stirred at room temperature for 30 min and concentrated. The crudematerial was purified by chromatography on silica gel, eluted with30-100% of ethyl acetate in hexanes, to give the desired product (9.1 g,100%).

Step 2:N-((6-aminopyridin-2-yl)sulfonyl)-2,4-dichloropyrimidine-5-carboxamide

A mixture of2,4-dichloro-N-((6-nitropyridin-2-yl)sulfonyl)pyrimidine-5-carboxamide(1.7 g, 4.5 mmol, 1.0 eq) and iron (2.6 g, 47 mmol, 10 eq) in HCl (1.9mL 23 mmol, 5.1 eq), ethanol (6 mL), tetrahydrofuran (6 mL), and water(0.90 mL) was heated at 60° C. for 1 hour. The reaction mixture wasfiltered through celite and washed with methanol and ethyl acetate. Thefiltrate was concentrated under reduced pressure to give the desiredcompound (1.7 g, 100%) LC-MS: (M+H)⁺=348.0.

Step 3:(S)-N-((6-aminopyridin-2-yl)sulfonyl)-2-chloro-4-(2,2,4-trimethylpyrrolidin-1-yl)pyrimidine-5-carboxamide

A mixture ofN-((6-aminopyridin-2-yl)sulfonyl)-2,4-dichloropyrimidine-5-carboxamide(0.60 g, 1.7 mmol, 1.0 eq), (S)-2,2,4-trimethylpyrrolidine hydrochloride(0.26 g, 1.8 mmol, 1.0 eq), and potassium carbonate (0.96 g, 7.0 mmol,4.0 eq) in 4.0 mL of dimethylsulfoxide was heated in a capped vial at125° C. for 20 hours. The reaction mixture was purified chromatographyon silica gel, and eluting with a gradient of 0-80% of methanol in ethylacetate to give(S)—N-((6-aminopyridin-2-yl)sulfonyl)-2-chloro-4-(2,2,4-trimethylpyrrolidin-1-yl)pyrimidine-5-carboxamideas a brown solid (0.22 g, 30% yield). ¹H NMR (DMSO-d₆, 250 MHz): δ 8.04(m, 1H), 7.48 (t, J=7.3 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.51 (d, J=8.3Hz, 1H), 6.25 (s, br, 2H), 2.99 (m, 1H), 2.84 (m, 1H), 2.14 (m, 1H),1.84 (m, 1H), 1.50 (s, 3H), 1.47 (s, 3H), 1.38 (m, 1H), 0.85 (d, J=6.3Hz, 3H) ppm. LC-MS: (M+H)⁺=424.9.

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-fluoro-5-isobutoxy-phenyl)-4-[(4S)-2,2,4-trimethylpyrrolidin-1-ylipyrimidine-5-carboxamide(Compound 2121)

ToN-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-4-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrimidine-5-carboxamide(70 mg, 0.1647 mmol),cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (12.05 mg, 0.01647mmol), and dioxane (840.0 μL) was added(3-fluoro-5-isobutoxy-phenyl)boronic acid (69.84 mg, 0.3294 mmol),followed by sodium carbonate (247.0 μL of 2 M, 0.4941 mmol) under anatmosphere of nitrogen. The reaction mixture was irradiated at 120° C.in the microwave for 1 hour. The reaction mixture was filtered and thenpurified directly by reverse-phase preparative chromatography utilizinga C18 column and HPLC-MS method 10-99 A1B1 (Acetonitrile-Water+5 mmolarHCl, 30 min method) to afford as a tan solid,N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-fluoro-5-isobutoxy-phenyl)-4-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrimidine-5-carboxamide(Compound 2121) (14 mg, 15%) ESI-MS m/z calc. 556.2268, found 557.2(M+1)⁺; Retention time: 1.71 minutes. 1H NMR (400 MHz, DMSO) δ 8.53 (s,1H), 7.73 (s, 3H), 7.70-7.63 (m, 1H), 7.59 (d, J=9.7 Hz, 1H), 7.21 (d,J=7.2 Hz, 1H), 7.07 (d, J=10.6 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 3.86 (d,J=6.6 Hz, 2H), 2.86-2.74 (m, 1H), 2.69 (t, J=10.9 Hz, 1H), 2.34-2.18 (m,1H), 2.13-1.99 (m, 1H), 1.95 (dd, J=11.9, 5.5 Hz, 1H), 1.63 (d, J=23.9Hz, 6H), 1.50 (t, J=12.2 Hz, 1H), 0.99 (d, J=6.7 Hz, 6H), 0.90 (d, J=6.3Hz, 3H).

PREPARATION 116:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2425) (Compound 2266) (racemic mixture)

In a 5 mL microwave vial was combined theN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-chloro-pyridine-3-carboxamide(85 mg, 0.2305 mmol) and fluorocesium (175.0 mg, 42.53 μL, 1.152 mmol)in DMSO (510.0 μL) followed by K₂CO₃ (318.6 mg, 2.305 mmol) and2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidine (169.0 mg, 0.9220 mmol).The vial was capped and heated to 150° C. in an oil bath for 16 hours.Additional fluorocesium (175.0 mg, 42.53 μL, 1.152 mmol), K₂CO₃ (318.6mg, 2.305 mmol) and 2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidine(169.0 mg, 0.9220 mmol) was added and heated to 165° C. for 16additional hours. The reaction mixture was filtered and then purifieddirectly by reverse-phase preparative chromatography utilizing a C18column and HPLC-MS method 10-99% acetonitrile-water+5 mmolar HCl toaffordN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2425) (Compound 2266) (80 mg, 66%)as a light yellow solid,ESI-MS m/z calc. 515.25665, found 516.2 (M₊1)⁺; Retention time: 1.31minutes. 1H NMR (400 MHz, DMSO) δ 12.47 (s, 1H), 7.70-7.52 (m, 2H), 7.17(dd, J=7.3, 0.5 Hz, 1H), 6.78-6.59 (m, 2H), 5.14 (s, 2H), 3.84 (d, J=3.5Hz, 2H), 3.30 (d, J=10.7 Hz, 2H), 2.84 (t, J=10.0 Hz, 1H), 2.68-2.55 (m,1H), 2.07 (s, 4H), 1.87-1.73 (m, 1H), 1.65 (dd, J=30.6, 10.5 Hz, 2H),1.55 (d, J=8.6 Hz, 6H), 1.49 (s, 3H), 1.28 (d, J=6.6 Hz, 10H). Thestereoisomers were separated using supercritical fluid chromatography ona ChiralPak AS-H (250×10 mm), 5 μm column using 12% MeOH in CO₂ at aflow rate of 10.0 mL/min. The separated enantiomers were separatelyconcentrated to dryness to give the pure compounds.

The following compounds can be prepared in the manner described herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-cyclopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2577) (Isomer 1, R or S stereoisomer) (Compound 2022)    (Isomer 2, R or S stereoisomer),-   N-[(6-amino-2-pyridyl)sulfonyl[-6-tert-butyl-2-[3-(cyclopropylmethyl)-2,2-dimethyl-pyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2242),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2,2-dimethyl-pyrrolidin-1-yl)-6-tert-butyl-pyridine-3-carboxamide    (Compound 1852),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-cyclopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2577) (Isomer 1, R or S stereoisomer) (Compound 2022)    (Isomer 2, R or S stereoisomer),-   N-[(6-amino-2-pyridyl)sulfonyl[-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2425) (Isomer 1, R or S stereoisomer) (Compound 2266)    (Isomer 2, R or S stereoisomer),-   6-tert-butyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(45)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1765)

PREPARATION 117:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclopentyl-1,2-dihydroxyethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl[pyridine-3-carboxamide(Isomer 1, R or S stereoisomer) andN-[(6-amino-2-pyridyl)sulfonyl[-6-tert-butyl-5-(2-cyclopentyl-1,2-dihydroxyethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl[pyridine-3-carboxamide(Isomer 2, R or S stereoisomer)

To a solution ofN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclopentylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1633) (8 mg, 0.01 mmol) in acetone (1.0 mL) and water (0.5mL), were added 4-methylmorpholine N-oxide (16 mg, 0.14 mmol) and osmiumtetroxide (15 μL of 2.5% w/v, 0.001 mmol), in that order, and thereaction mixture was stirred under air at ambient temperature. After 2h, the reaction mixture turned to a clear solution, and was concentratedto a light yellow paste. The paste was dissolved in DMSO (1 mL) andpurified by reverse-phase HPLC-MS method to furnish the twodiastereomeric diols as white solids. Isomer 1:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclopentyl-1,2-dihydroxy-ethyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(HCl salt) (2 mg, 23%) ESI-MS m/z calc. 573.29846, found 574.4 (M+1)⁺;Retention time: 1.51 minutes; Isomer 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclopentyl-1,2-dihydroxy-ethyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(HCl salt) (4 mg, 47%) ESI-MS m/z calc. 573.29846, found 574.4 (M+1)⁺;Retention time: 1.55 minutes

The following compounds can be prepared in the manner as describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclopentyl-1,2-dihydroxyethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2661) (Isomer 1),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1,2-dihydroxy-3,3-dimethylbutyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2069) (Isomer 2),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclohexyl-1,2-dihydroxyethyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (isomer 1),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclohexyl-1,2-dihydroxyethyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (isomer 2),

PREPARATION 118:6-methoxy-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide(Compound 2419) Step 1:2-chloro-6-methoxy-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]quinoline-3-carboxamide

2-Chloroquinoline-3-carboxylic acid (62 mg, 0.3 mmol) and CDI (73 mg,0.5 mmol) were combined in DMF (2 mL) and stirred at 40° C. for 2 hours.In a separate vial, NaH (15 mg, 0.4 mmol) was added to2-methoxypyridine-3-sulfonamide (71 mg, 0.4 mmol) in DMF (1 mL). Thesolutions were combined and stirred overnight at ambient temperature.The reaction mixture was taken up in EtOAc and washed with HCl (1 N, 1×5mL). The aqueous layer was back washed with EtOAc (2×10 mL), thecombined organic layers were washed with brine (1×10 mL) and dried oversodium sulfate, filtered and concentrated under reduced pressure. Thesolid was dissolved in 1,4-dioxane (2 mL) with 4M HCl (750 uL, 4.0 mmol)and heated to 90° C. for 2 hours. The reaction mixture was cooled, thesolvent was removed under reduced pressure to yield a solid, which wastriturated with ethyl acetate to give the desired compound (89 mg, 79%).ESI-MS m/z 394.2 (M+1)⁺, retention time 0.39 minutes.

Step 2:6-methoxy-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide(Compound 2419) (Compound 2405)

2-Chloro-N-methylsulfonyl-quinoline-3-carboxamide (40 mg, 0.1 mmol),potassium carbonate (69 mg, 0.5 mmol), and(4S)-2,2,4-trimethylpyrrolidine (HCl salt) (30 mg, 0.2 mmol) wassuspended in DMSO (1 mL). The reaction was heated at 120° C. for 2 days,then cooled, diluted with DMSO-methanol, filtered, and then purified viareverse phase HPLC-MS method using a dual gradient run from 1-99% mobilephase B over 15.0 minutes (mobile phase A=H₂O (5 mM TFA), mobile phaseB=acetonitrile) to give the desired compound (8 mg, 17%). ESI-MS m/z471.3 (M+1)⁺, retention time 1.19 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   6-methyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide    (Compound 2471),-   N-[(6-amino-2-pyridyl)sulfonyl]-7-methyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide    (Compound 2519),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-methoxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide    (Compound 2196),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-methyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide    (Compound 2548),-   N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide    (Compound 2405),-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide    (Compound 2265) and-   N-[(2-methoxy-3-pyridyl)sulfonyl]-7-methyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]quinoline-3-carboxamide    (Compound 1859)

PREPARATION 119:N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-isopropoxy-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2230) Step 1:N-[(6-amino-2-pyridyl)sulfonyl]-2,6-dichloro-5-fluoro-pyridine-3-carboxamide

2,6-Dichloro-5-fluoro-pyridine-3-carboxylic acid (5.0 g, 23.8 mmol), CDI(6.8 g, 41.9 mmol) and DMF (30 mL) were stirred at 60° C. for 50 min. Ina separate flask, 6-aminopyridine-2-sulfonamide (5.2 g, 29.8 mmol), NaH(1.2 g, 29.8 mmol), and DMF (25 mL). The reaction mixture was stirred at60° C. for 1 hour. The contents containing 6-aminopyridine-2-sulfonamidewas added dropwise to the activated acid at room temperature. Thereaction mixture was stirred for 16 hours at room temperature. Thereaction mixture was then placed in an ice bath, diluted with water (300mL), and adjusted pH to 2. The resulting slurry was vigorously stirredfor 30 min. The precipitate was filtered, washed with water (50 ML×3)and hexanes (50 mL×3), and dried in vacuo to furnishN-[(6-amino-2-pyridyl)sulfonyl]-2,6-dichloro-5-fluoro-pyridine-3-carboxamide(6.9 g, 79%).

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-5-fluoro-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide

To a solution ofN-[(6-amino-2-pyridyl)sulfonyl]-2,6-dichloro-5-fluoro-pyridine-3-carboxamide(1.0 g, 2.7 mmol) in DMSO (8 mL) was added 2,2,4-trimethylpyrrolidine(HCl salt) (820 mg, 5.5 mmol) and K₂CO₃ (2.3 g, 16.4 mmol). The reactionwas stirred at 150° C. for 16 hours. The reaction mixture was filteredand purified via prep HPLC (1-99% ACN, 15 min, HCl modifier) to affordN-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-5-fluoro-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(HCl salt) (200 mg, 30%).

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-isopropoxy-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2230)

N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-5-fluoro-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(HCl salt) (50 mg, 0.10 mmol), isopropanol (31mg, 40 μL, 0.52 mmol), NaH(10 mg, 0.24 mmol), and DMSO (1mL). The reaction mixture was stirred at150° C. for 2 hours. The reaction mixture was then filtered and purifiedvia prep HPLC (1-99% ACN, 15min, HCL modifier) to yieldN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-isopropoxy-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2230) (HCl salt) (13 mg, 23%) 1H NMR (400 MHz, DMSO-d6) δ12.26 (s, 1H), 7.66-7.55 (m, 2H), 7.17 (dd, J=7.3, 0.7 Hz, 1H), 6.66(dd, J=8.4, 0.8 Hz, 1H), 6.41 (s, 2H), 5.26 (p, J=6.1 Hz, 1H), 2.60-2.51(m, 1H), 2.49-2.40 (m, 1H), 2.33 (p, J=1.8 Hz, OH), 2.20 (s, 1H), 1.84(dd, J=11.8, 5.6 Hz, 1H), 1.51 (s, 3H), 1.45 (s, 3H), 1.43-1.30 (m, 4H),1.29 (d, J=6.2 Hz, 3H), 0.85 (d, J=6.3 Hz, 3H). ESI-MS m/z calc.465.1846, found 466.3 (M+1)⁺; Retention time: 1.38 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1-cyclopropylethoxy)-5-fluoro-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2373) and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2-dimethylpropoxy)-5-fluoro-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1810)

PREPARATION 120:N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(p-tolyl)pyridine-3-carboxamide(Compound 2276) Step 1:2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid

2,6-Dichloropyridine-3-carboxylic acid (1.000 g, 4.861 mmol) in IPA (30mL), K₂CO₃ (6.075 mL of 2 M, 12.15 mmol) anddichloropalladium;triphenylphosphane (341.2 mg, 0.4861 mmol) was added.The reaction mixture was heated to 80° C. under an atmosphere ofnitrogen and (3-fluoro-5-isobutoxy-phenyl)boronic acid (1.082 g, 5.104mmol) in IPA (30 mL) was added slowly over 1 hour. The reaction mixturewas heated for a further 4 h. The reaction mixture was cooled, 6 M HCl(2 mL) was added and then pH adjusted to 2-3 with additional 6 M HCl.The organic phase was collected, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by reverephase column chromatography using 10-80% ACN in Water (with TFAmodifier) to give the desired compound. ESI-MS m/z 324.0 (M₊1)⁺;Retention time: 1.0 minutes.

Step 2: 6-(3-fluoro-5-isobutoxy-phenyl)-2-(p-tolyl)pyridine-3-carboxylicacid

A mixture of2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (324mg, 1.00 mmol), p-tolylboronic acid (272 mg, 2.00 mmol), K₂CO₃ (415 mg,3.00 mmol), and tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.10mmol) in DMF (10 mL) was degassed under a stream of nitrogen and stirredat 120° C. for 16 hours. A further aliquot oftetrakis(triphenylphosphine)palladium (0) (116 mg, 0.10 mmol) was added,and the reaction mixture was stirred at 150° C. for 17 hours. Thereaction mixture was diluted with water, adjusted to pH 5 with 1 M HCl,and extracted with ethyl acetate. The combined extracts were washed withbrine, dried over sodium sulfate, and evaporated under reduced pressure.The residue was purified by silica gel chromatography using 0-5%methanol in dichloromethane as eluent to give6-(3-fluoro-5-isobutoxy-phenyl)-2-(p-to/y/)pyridine-3-carboxylic acid(314 mg, 83%).

Step 3:N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(p-tolyl)pyridine-3-carboxamide(Compound 2276)

A solution of 6-(3-fluoro-5-isobutoxyphenyl)-2-(p-tolyl)nicotinic acid(38 mg, 0.1 mmol) and N-(oxomethylene)sulfamoyl chloride (17 mg, 10 μL,0.1 mmol) in dichloromethane (1 mL) was stirred for an hour, thentent-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (28 mg, 0.2 mmol) andtriethylamine (15 mg, 21 4, 0.2 mmol) were added. After 17 hours, HCl(200 μL of 4 M, 0.8 mmol) (in dioxane) was added, and the reactionmixture was stirred for two hours. The reaction mixture was filtered andpurified using a reverse phase HPLC-MS method using a Luna C18 (2)column (75×30 mm, 5 μm particle size) and a dual gradient run from 1-99%mobile phase B over 15.0 minutes (mobile phase A=H₂O (5 mM HCl), mobilephase B=CH₃CN. Flow rate=50 mL/min, and column temperature=25° C.) togive the desired compound. ESI-MS m/z 527.4 (M+1)⁺; Retention time: 1.62minutes.

PREPARATION 121:N-[(2-acetamido-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1976)

N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(80 mg, 0.1525 mmol) in pyridine (800 μL, 9.891 mmol) was treated withacetic anhydride (400 μL, 4.239 mmol) and stirred at room temperatureovernight. The product was isolated by prep. HPLC to giveN-[(2-acetamido-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1976) (HCl salt) (20 mg, 21%) 1H NMR (400 MHz, DMSO-d6) δ8.85(s, 1H), 8.67 (d, J=4.7 Hz, 1H), 8.43 (d, J=7.9 Hz, 1H), 8.30 (d, J=9.0Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.53-7.42 (m, 1H), 7.28 (d, J=8.0 Hz,1H), 6.87 (d, J=8.7 Hz, 1H), 5.31 (p, J=6.3 Hz, 1H), 2.41 (s, 2H), 2.25(s, 3H), 2.18 (dt, J=16.2, 7.6 Hz, 1H), 1.88 (dd, J=12.1, 5.8 Hz, 1H),1.55 (d, J=4.4 Hz, 6H), 1.42 (t, J=12.0 Hz, 1H), 1.31 (d, J=6.1 Hz, 6H),0.74 (d, J=6.3 Hz, 3H). ESI-MS m/z calc. 566.23114, found 567.0 (M+1)⁺;Retention time: 2.19 minutes.

PREPARATION 122:N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-ethoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2256) Step 1:2-chloro-6-(6-fluoro-4-methyl-2-pyridyl)pyridine-3-carboxylic acid

2,6-Dichloronicotinic acid (661 mg, 3.44 mmol),(6-fluoro-4-methyl-2-pyridyl)boronic acid (560 mg, 3.62 mmol), K₂CO₃(4.13 mL of 2 M, 8.26 mmol) in IPA (20 mL) was added Pd(PPh₃)₂Cl₂ (48.3mg, 0.07 mmol). The reaction mixture was placed under an atmosphere ofnitrogen and heated to 80° C. for 10 h. The reaction mixture wasfiltered, the solvent was evaporated under reduced pressure and thecrude mixture was purified by reverse phase column chromatography using10-80% acetonitrile in water (TFA modifier) to give the desiredcompound. ESI-MS m/z 267.0 (M+1)⁺; Retention time: 0.82 minutes.

Step 2: 2-chloro-6-(6-ethoxy-4-methyl-2-pyridyl)pyridine-3-carboxylicacid

2-chloro-6-(6-fluoro-4-methyl-2-pyridyl)pyridine-3-carboxylic acid (4.2g, 15 mmol) was dissolved into a solution of sodium ethoxide (25 mL of21% w/v, 79 mmol) in ethanol. The reaction mixture was heated to 75° C.and stirred for 3 hours. The reaction mixture was diluted with EtOAc (75mL) and washed with water (1×75 mL) with some brine (20 mL). The aqueouslayer was extracted with EtOAc (1×75 mL). The organic layers werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure to give an orange solid. The solid was redissolved inEtOAc (75 mL) and aqueous NaOH solution (1 M, 75 mL). The aqueous layerwas isolated and acidified to pH 2, extracted with EtOAc (2×75 mL). Thefinal organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The obtained solid was purified bysilica gel column chromatography column, using 0-10% MeOH/DCM as eluentto give 2-chloro-6-(6-ethoxy-4-methyl-2-pyridyl)pyridine-3-carboxylicacid (1.17 g, 25%) as a white solid. ESI-MS m/z calc. 292.06146, found293.1 (M+1)⁺; Retention time: 1.72 minutes.

Step 3:N-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(6-ethoxy-4-methyl-2-pyridyl)pyridine-3-carboxamide

2-chloro-6-(6-ethoxy-4-methyl-2-pyridyl)pyridine-3-carboxylic acid (200mg, 0.68 mg) was dissolved in DMF (2.5 mL). CDI (123 mg, 0.75 mmol) wasadded, and the reaction mixture was allowed to stir at 60° C. for 1hour. In a separate flask, sulfonamide was dissolved in DMF (600 μL),and NaH (34 mg, 0.85 mmol) was added and the reaction mixture wasstirred for 45 minutes at room temperature. The activated carboxylicacid mixture was then added to the deprotonated sulfonamide. The finalreaction mixture was stirred at 60° C. overnight. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc (50 mL) andwashed with water (1×50 mL) and brine (2×75 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure to give the desired compound (297 mg, 97%). ESI-MS m/z 448.0(M+1)⁺; Retention time: 0.53 minutes.

Step 4:N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-ethoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2256)

2-chloro-6-(6-ethoxy-4-methyl-2-pyridyl)-N-methylsulfonyl-pyridine-3-carboxamide(60 mg, 0.13 mmol) and (4S)-2,2,4-trimethylpyrrolidine (free base, 45mg, 0.4 mmol) were combined in DMSO (100 μL). Potassium carbonate (55mg, 0.4 mmol) was added and the reaction mixture was heated overnight at140° C., then 165° C. for 3 hours. The reaction mixture was purifiedusing a reverse phase HPLC method using a Luna C18 (2) column (50×21.2mm, 5 μm particle size) and a dual gradient run from 10-99% mobile phaseB over 15.0 minutes (mobile phase A=water (de-ionized, no acidmodifier), mobile phase B=acetonitrile) to give the desired compound.ESI-MS m/z 525.3 (M₊1)⁺; Retention time: 1.57 minutes.

PREPARATION 123:N-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(diethylamino)-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1845) Step 1:N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-fluoro-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

A mixture ofN-[(2-amino-3-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(0.12 g, 0.28 mmol), (6-fluoro-2-pyridyl)boronic acid (0.06 g, 0.42mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (0.02 g, 0.02 mmol), and Na₂CO₃ (0.09 g,0.85 mmol) in DMF (2.2 mL) and water (566 μL) was degassed under astream of nitrogen and stirred at 100° C. for 20 hours. The reactionmixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over sodium sulfate, andevaporated under reduced pressure. The residue was purified by silicagel column chromatography using 0-5% methanol in dichloromethane aseluent to giveN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-fluoro-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(0.11 g, 80%) as yellow solid.

Step 2:N-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(diethylamino)-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1845)

A solution ofN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-fluoro-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-ylipyridine-3-carboxamide(30 mg, 0.06 mmol) and diethylamine (1 mL, 9.67 mmol) was stirred in asealed vessel at 120° C. for 17 hours, then 150° C. for 22 hours. Thediethylamine was removed under vacuum, and the residue was purifiedusing a reverse phase HPLC-MS method using a Luna C18 (2) column (75×30mm, 5μm particle size) and a dual gradient run from 25-75% mobile phaseB over 15.0 minutes (mobile phase A=H₂O (5 mM HCl), mobile phaseB=CH₃CN) to give the desired compound. ESI-MS m/z 483.5 (M+1)⁺;Retention time: 0.88 minutes

The following compounds can be synthesized using the proceduresdescribed herein

-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropylamino)-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2500),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-5-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 1907),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isobutylamino)-5-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide    (Compound 2362),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-4-methyl-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2002),-   6-(6-ethoxy-4-methyl-2-pyridyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2487),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethoxy]-4-methyl-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1696),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-isopropoxyethoxy)-4-methyl-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1703),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-ethoxyethoxy)-4-methyl-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1700),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isopropyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2687),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isopropylamino)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2688)-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[ethyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2689),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-ethoxyethyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2685),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethyl-methyl-amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2684) and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-ethoxyethylamino)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2686).

PREPARATION 124:N-(benzenesulfonyl)-6-(6-ethoxy-4-methyl-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 2455)

N-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(6-ethoxy-4-methyl-2-pyridyl)pyridine-3-carboxamide(50 mg, 0.1 mmol) and 2,4,6-trimethyl-phenol (45 mg, 0.3 mmol) weredissolved in DMSO (175 μL) and dioxane (175 μL). Sodium hydride (13mg,0.3 mmol) was added and the reaction mixture was heated under microwaveirradiation at 150° C. for 20 minutes. The reaction mixture was purifiedusing a reverse phase HPLC method using a Luna C18 (2) column (50×21.2mm, 5 μm particle size) and a dual gradient run from 10-99% mobile phaseB over 15.0 minutes (mobile phase A=water (de-ionized, no acidmodifier), mobile phase B=acetonitrile) to giveN-(benzenesulfonyl)-6-(6-ethoxy-4-methyl-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 2455). ESI-MS m/z 532.5 (M+1)⁺; Retention time: 2.52 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-4-methyl-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 2511),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-ethoxy-4-methyl-2-pyridyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1795),-   6-(6-ethoxy-4-methyl-2-pyridyl)-N-(1H-pyrazol-3-ylsulfonyl)-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 2301) and-   6-(6-ethoxy-4-methyl-2-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide    (Compound 1768).

PREPARATION 125:N-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1697) Step1:N-[(2-amino-3-pyridyl)sulfonyl]-2,6-dichloro-pyridine-3-carboxamide

2,6-dichloropyridine-3-carboxylic acid (1.5 g, 7.8 mmol) and CDI (1.9 g,11.7 mmol) in DMF (17 mL) was stirred at 60° C. In a separate vial,2-aminopyridine-3-sulfonamide (1.7 g, 9.8 mmol) and NaH (0.4 g, 9.8mmol) in DMF (8 mL) was stirred at ambient temperature. The two reactionmixtures were combined and stirred overnight at room temperature. Thereaction mixture was taken up in EtOAc and washed with HCl (1 N, 1×25mL) and the aqueous layer was washed with EtOAc (4×20 mL). The combinedorganic layers were washed with brine (1×15 mL) and dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting solid that crashed was washed with ethyl acetate and themother liquor was concentrated, the residue was washed with ethylacetate and hexanes to obtainN-[(2-amino-3-pyridyl)sulfonyl]-2,6-dichloro-pyridine-3-carboxamide (2.5g, 94%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.28-8.12 (m, 2H),8.07 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 6.87 (dd, J=7.7, 5.4 Hz,1H).

Step 2:N-[(2-amino-3-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

DMSO (17 mL) was added toN-[(2-amino-3-pyridyl)sulfonyl]-2,6-dichloro-pyridine-3-carboxamide (2.1g, 6.0 mmol), (4S)-2,2,4-trimethylpyrrolidine (HCl salt) (1.1 g, 7.3mmol), and potassium carbonate (3.3g, 24 mmol). The reaction mixture wassealed and stirred at 120° C. for 2 days. The reaction mixture wasallowed to cool and then diluted with ethyl acetate (40 mL) and water(60 mL). To the aqueous layer, aq HCl was added to pH 7 and then washedwith ethyl acetate (5×50 mL). The combined organic layers wereconcentrated to half volume then washed with brine and dried over sodiumsulfate, filtered and evaporated under reduced pressure to giveN-[(2-amino-3-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(2.5 g, 100%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (dd,J=4.8, 1.8 Hz, 1H), 8.06 (dd, J=7.9, 1.8 Hz, 1H), 7.71 (d, J=7.9 Hz,1H), 6.79 (dd, J=7.9, 4.8 Hz, 1H), 6.64 (d, J=7.9 Hz, 1H), 2.46-2.34 (m,2H), 2.19-2.03 (m, 1H), 1.82 (dd, J=12.1, 5.6 Hz, 1H), 1.47 (d, J=3.3Hz, 6H), 1.36 (t, J=12.2 Hz, 1H), 0.74 (d, J=6.3 Hz, 3H).

Step 3:N-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-dihydro-2H-pyran-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1699)

N-[(2-amino-3-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(32 mg, 0.08 mmol),2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(19 mg, 0.09 mmol), and1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazole; 3-chloropyridine;dichloropalladium (3 mg, 0.005 mmol, 5 mol %) was dissolved in EtOH (600μL) and solution of potassium carbonate (150 μL, 2M) was added. Thereaction mixture was heated at 120° C. for 16 hours under an atmosphereof nitrogen. The reaction mixture was cooled, filtered and purified viaLC/MS utilizing a gradient of 25-75% acetonitrile in 5 mM aq HCl. Sodiumcarbonate was added to collected fractions (pH 7-8) and the solventswere removed to dryness to yield the desired compound. ESI-MS m/z 472.3(M₊1)⁺; Retention time: 1.18 minutes

Step 4:N-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl[pyridine-3-carboxamide(Compound 2351)

ToN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-dihydro-2H-pyran-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl[pyridine-3-carboxamide(Compound 1699) (37 mg, 0.08 mmol) in EtOH (3 mL), palladium on carbon(8 mg, 0.008 mmol, 10w/w %) was added. The reaction mixture was stirredunder an atmosphere of hydrogen 16 hours at ambient temperature. Thereaction mixture was filtered and evaporated to dryness, dissolved inDMSO-methanol and purified via reverse phase HPLC-MS method using a dualgradient run from 1-99% mobile phase B over 15.0 minutes. Mobile phaseA=H₂O (5 mM TFA) Mobile phase B=acetonitrile to yieldN-[(2-amino-3-pyridyl)sulfonyl[-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2351). ESI-MS m/z 474.4(M+1)⁺; Retention time: 1.15 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(1,2-dimethylpropyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1911)-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(5,5-dimethyl-2-oxo-cyclohexyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl[pyridine-3-carboxamide    (Compound 1793)-   N-[(2-amino-3-pyridyl)sulfonyl]-6-norbornan-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2097)-   N-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-4-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1850)-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-cyclopropylethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2553)-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-5,5-dimethyl-cyclohexyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2047)-   N-(benzenesulfonyl)-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1868)-   N-(benzenesulfonyl)-6-isobutyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2246)-   N-(benzenesulfonyl)-6-tetrahydrofuran-3-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2277)-   N-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-3-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2311)-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-bicyclo[2.2.1]hept-2-enyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2709)-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2077) (Isomer 1, cis or trans stereoisomer)-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2432) (Isomer 2, cis or trans stereoisomer).

PREPARATION 126:N-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2351) (Isomer 1, RS or SS stereoisomer) andN-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2351) (Isomer 2, RS or SS stereoisomer)

The stereoisomers were separated using supercritical fluidchromatography on a Phenomenex LUX-4 (250×10 mm), 5 μm column using 48%EtOH/IPA (50/50) in CO₂ at a flow rate of 10.0 mL/min. The separatedenantiomers were separately concentrated to dryness to give the purecompounds. SFC Peak 1:N-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2351) ESI-MS m/z 474.4(M₊1)⁺; Retention time: 1.15 minutes.SFC Peak 2:N-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2351) ESI-MS m/z 474.4(M+1)⁺; Retention time: 1.15 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[2-tetrahydropyran-2-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2672) (Isomer 1, RS or SS stereoisomer) and-   N-[(2-amino-3-pyridyl)sulfonyl]-6-[2-tetrahydropyran-2-yl]-2-[(4    S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2675) (Isomer 2, RS or SS stereoisomer).

PREPARATION 127:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-cyclopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2577) (Compound 2022) (Isomer 1, R or S stereoisomer) andN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-cyclopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2577) (Compound 2022) (Isomer 2, R or S stereoisomer)

The stereoisomers were separated using supercritical fluidchromatography on a ChiralPak AD-H (250×10 mm), 5 μm column using 22%EtOH/MeOH (90:10, 20 mM NH₃) in CO₂ at a flow rate of 10.0 mL/min. Theseparated enantiomers were separately concentrated, diluted with ethylacetate (3 mL) and washed with 1N aqueous hydrochloric acid. The organiclayers were dried over sodium sulfate, filtered, and evaporated todryness to give the pure compounds. SFC Peak 1:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-cyclopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2577) (Compound 2022) 1H NMR (400 MHz, DMSO) δ 12.35 (s, 1H),7.59 (d, J=7.7 Hz, 2H), 7.14 (d, J=6.7 Hz, 1H), 6.73-6.58 (m, 2H), 6.43(s, 2H), 2.79 (s, 1H), 2.62 (s, 1H), 1.80-1.59 (m, 2H), 1.56 (s, 3H),1.51 (s, 3H), 1.27 (s, 9H), 1.13-1.03 (m, 1H), 0.71-0.58 (m, 1H),0.56-0.46 (m, 1H), 0.46-0.33 (m, 1H), 0.24 (td, J=9.2, 5.0 Hz, 1H),0.12-0.01 (m, 1H). SFC Peak 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-cyclopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2577) (Compound 2022) 1H NMR (400 MHz, DMSO) δ 12.35 (s, 1H),7.58 (d, J=7.1 Hz, 2H), 7.14 (d, J=7.1 Hz, 1H), 6.77-6.56 (m, 2H), 6.42(s, 2H), 2.79 (s, 1H), 2.66 (dd, J=12.3, 10.5 Hz, 1H), 1.69 (d, J=20.9Hz, 2H), 1.56 (s, 3H), 1.51 (s, 3H), 1.27 (s, 9H), 1.17-1.05 (m, 1H),0.73-0.63 (m, 1H), 0.58-0.47 (m, 1H), 0.40 (dd, J=8.2, 3.9 Hz, 1H), 0.24(dd, J=9.0, 4.1 Hz, 1H), 0.07 (dd, J=9.0, 4.0 Hz, 1H).

PREPARATION 128:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2425) (Compound 2266) (Isomer 1, R or S stereoisomer) andN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2425) (Compound 2266) (Isomer 2, R or S stereoisomer)

The stereoisomers were separated using supercritical fluidchromatography on a ChiralPak AD-H (250×10 mm), 5 μm column using 12%MeOH in CO₂ at a flow rate of 10.0 mL/min. The separated enantiomerswere separately concentrated, diluted with ethyl acetate (3 mL) andwashed with 1N aqueous hydrochloric acid. The organic layers were driedover sodium sulfate, filtered, and evaporated to dryness to give thepure compounds. SFC Peak 1:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2425) (Compound 2266) ESI-MS m/z calc. 515.25665, found 516.2(M+1) ; Retention time: 1.31 minutes. SFC Peak 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2425) (Compound 2266) ESI-MS m/z calc. 515.25665, found 516.2(M+1) ; Retention time: 1.31 minutes . 1H NMR (400 MHz, DMSO) δ 12.48(s, 1H), 7.70-7.52 (m, 2H), 7.17 (dd, J=7.3, 0.5 Hz, 1H), 6.70 (dd,J=9.7, 8.5 Hz, 2H), 5.19 (s, 2H), 3.84 (td, J=11.1, 3.7 Hz, 2H),3.38-3.18 (m, 2H), 2.84 (t, J=10.0 Hz, 1H), 2.68-2.55 (m, 1H), 2.07 (s,4H), 1.81 (t, J=6.4 Hz, 1H), 1.65 (dd, J=30.6, 10.5 Hz, 2H), 1.55 (d,J=8.6 Hz, 6H), 1.49 (s, 3H), 1.28 (d, J=6.6 Hz, 10H).

PREPARATION 129:N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2532) (Isomer 1) (Compound 2178) (Isomer 2) (Compound 2062)(Isomer 3) (Compound 1863) (Isomer 4) Step 1:N-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide

2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (3.91g, 9.66 mmol) was dissolved in DMF (31 mL) was stirred under nitrogenand CDI (2.35 g, 14.5 mmol) was added in one portion. The reactionmixture was warmed to 65° C. and heated for 1 h. Meanwhile in a separatevessel, 6-aminopyridine-2-sulfonamide (2.09 g, 12.1 mmol) was slurriedin DMF (15 mL) under nitrogen and NaH (483 mg, 12.1 mmol) addedportionwise to mitigate gas evolution and the reaction was stirred for 1h. The two reactions were combined in one portion at 65° C. The reactionwas stirred for 15 min and evaporated. The reaction mixture was pouredover ice and acidified (ph=4) by the addition of 6M HCl. The resultingmixture was extracted with ethyl acetate (1 L). The organics were washedwith brine (2×500 mL), dried over sodium sulfate and evaporated underreduced pressure. The crude material was purified by silica gel columnchromatography eluting with 0-100% ethyl acetate in hexanes to giveN-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(4.02 g, 887%) ESI-MS m/z calc. 478.08777, found 479.1 (M+1)⁺; Retentiontime: 0.7 minutes.

Step2:N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2532) (Compound 2178) (Compound 2062) (Compound 1863)

N-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(100 mg, 0.21 mmol) and fluorocesium (156 mg, 38.5 μL, 1.04 mmol) inDMSO (600 μL) followed by K₂CO₃ (289 mg, 2.09 mmol) and3,4-dimethylpiperidine (118 mg, 1.04 mmol). The reaction mixture wassealed and heated to 150° C. overnight, then 165° C. for 6 hours. Thereaction mixture was filtered and then purified directly byreverse-phase HPLC-MS using 10-99% Acetonitrile-Water+5 mmolar HCl aseluent to affordN-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2532) (Compound 2178) (Compound 2062) (Compound 1863) (86 mg,74%), as a light yellow solid ESI-MS m/z calc. 555.23157, found 556.2(M+1)⁺; Retention time: 2.0 minutes. 1H NMR (400 MHz, DMSO) δ 12.66 (s,1H), 7.81 (d, J=7.9 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.50-7.41 (m, 3H),7.22 (d, J=7.3 Hz, 1H), 6.91 (d, J=10.9 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H),6.47 (s, 1H), 3.85 (d, J=6.5 Hz, 2H), 3.51 (d, J=8.5 Hz, 1H), 3.40 (d,J=12.8 Hz, 1H), 3.13 (d, J=11.8 Hz, 1H), 2.97 (d, J=6.0 Hz, 1H), 2.06(d, J=9.3 Hz, 1H), 1.89-1.72 (m, 2H), 1.42 (s, 2H), 1.00 (d, J=6.7 Hz,6H), 0.87 (d, J=6.6 Hz, 3H), 0.77 (d, J=6.6 Hz, 3H

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2532) (Compound 2178) (Compound 2062) (Compound 1863) (Isomers1-4, RR, RS, SS, or SR stereoisomer)

The stereoisomers were separated using supercritical fluidchromatography on a ChiralCel OZ-H (250×10 mm), 5 μm column using 25%MeOH:EtOH 50:50 in CO₂ at a flow rate of 10.0 mL/min. The separatedenantiomers were separately concentrated to give the pure compound. SFCPeak 1:N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2532) (Compound 2178) (Compound 2062) (Compound 1863) ESI-MSm/z calc. 555.23157, found 556.2 (M₊1)⁺; Retention time: 2.02 minutes.SFC Peak 2(N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2532) (Compound 2178) (Compound 2062) (Compound 1863) ESI-MSm/z calc. 555.23157, found 556.2 (M+1)⁺; Retention time: 2.01 minutes.SFC Peak 3N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,4-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 2532) (Compound 2178) (Compound 2062) (Compound 1863) ESI-MSm/z calc. 555.23157, found 556.2 (M+1)⁺; Retention time: 1.96 minutes.SFC Peak 4 ESI-MS m/z calc. 555.23157, found 556.2 (M+1)⁺; Retentiontime: 1.96 minutes. 1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 7.79 (d,J=7.8 Hz, 1H), 7.63 (t, J=10.7 Hz, 1H), 7.45 (d, J=11.6 Hz, 3H), 7.20(d, J=6.5 Hz, 1H), 6.90 (d, J=10.7 Hz, 1H), 6.70 (d, J=7.1 Hz, 1H), 6.44(s, 2H), 3.84 (d, J=6.5 Hz, 2H), 3.50 (s, 1H), 3.38 (s, 1H), 3.12 (d,J=13.0 Hz, 1H), 2.96 (s, 1H), 2.08-1.98 (m, 1H), 1.80 (s, 2H), 1.41-1.37(m, 1H), 1.30-1.22 (m, 1H), 1.00 (d, J=6.7 Hz, 7H), 0.86 (d, J=6.5 Hz,4H), 0.76 (d, J=6.6 Hz, 3H).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethyl-1-piperidyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2451) (Compound 1993) (Compound 1864) (Compound 1855)    (Isomers 1-4, stereoisomers RR, RS, SS, SR), using as SFC ChiralCel    OZ-H (250×10 mm), 5 μm column and eluent 25% MeOH (20 mM NH₃) in CO2-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(6-methyl-8-azaspiro[3.4]octaN-8-yl)pyridine-3-carboxamide    (Compound 2552) (Isomer 1, R or S stereoisomer) (Compound 2269)    (Isomer 2, R or S stereoisomer), using as SFC ChiralPak IA (250×10    mm), 5pm column and eluent 22% EtOH (0.1% TFA) in CO2-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-2,4-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2213) (Compound 2058) (Compound 1817) (Compound 1729)    (Isomers 1-4, stereoisomers RR, RS, SS, SR), using as SFC ChiralCel    OZ-H (250×10 mm), 5pm column and eluent 22% IPA:EtOH 50:50 in CO₂-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-(trifluoromethyppyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2271) (Isomer 1, R or S stereoisomer) using as SFC    ChiralCel OZ-H (250×10 mm), 5μm column and eluent 25% MeOH:EtOH    (50:50) in CO₂.

PREPARATION 130:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-5-iodo-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2009)

N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(100 mg, 0.18 mmol) was dissolved in CH₂Cl₂ (700 μL) and was treatedwith 1-iodopyrrolidine-2,5-dione (44 mg, 0.19 mmol). The reactionmixture was allowed to stir at 40° C. for 30 minutes. The volatiles wereevaporated under a slow stream of nitrogen gas. The remaining residuewas redissolved in DMSO, filtered and purified by reverse-phase HPLCusing a Luna C18 (2) column (50×21.2 mm, 5 μm particle size) and a dualgradient run from 30-99% mobile phase B over 15.0 minutes (mobile phaseA=water (de-ionized, no acid modifier), mobile phase B =acetonitrile) togive the desired compound. ESI-MS m/z calc. 681.1282, found 682.2(M+1)⁺; Retention time: 2.26 minutes.

PREPARATION 131:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-methyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2258)

N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(500 mg, 0.90 mmol) in DMF (5 mL) was treated with Cs₂CO₃ (352 mg, 1.1mmol) and the reaction mixture was stirred for 0.5 h at roomtemperature, then cooled in an ice bath and treated with MeI (141 mg, 61μL, 1.0 mmol). The reaction mixture was stirred overnight at roomtemperature. The suspension was added to water (25 ml), stirred at roomtemperature for 1 h and the suspension was filtered and washed withwater. The solid was purified by silica gel column chromatography usingas dichloromethane as eluent to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-methyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2258) (315 mg, 61%). ESI-MS m/z 570.0 (M+1)⁺; Retention time:3.4 minutes ; 1H NMR (400 MHz, DMSO-d6) δ 7.67-7.54 (m, 2H), 7.49 (t,J=1.8 Hz, 1H), 7.40 (dt, J=10.2, 1.8 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),7.06 (d, J=7.3 Hz, 1H), 6.89 (dt, J=10.7, 2.3 Hz, 1H), 6.70 (d, J=8.4Hz, 1H), 6.64 (s, 2H), 3.84 (d, J=6.7 Hz, 2H), 3.43 (s, 3H), 2.82 (s,1H), 2.64 (s, 1H), 2.34-2.22 (m, 1H), 2.05 (hept, J=6.6 Hz, 1H), 1.91(dd, J=11.9, 5.7 Hz, 1H), 1.62 (d, J=4.4 Hz, 6H), 1.46 (t, J=12.1 Hz,1H), 0.99 (d, J=6.7 Hz, 6H), 0.94 (d, J=6.3 Hz, 3H)

PREPARATION 132:N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-[3-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]pyridine-3-carboxamide(Compound 1890) Step 1:1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-2-ol

To a suspension of 1-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-2-ol(25.0 g, 95 mmol), Bis(pinacolato)diboron (26.5 g, 105 mmol), and KOAc(18.7 g, 190 mmol) in dioxane (375 mL) under an atmosphere of nitrogenwas added Pd(dppf)Cl₂.DCM (768 mg, 1.0 mmol) and the reaction mixturewas heated to 103° C. for 2 hours, cooled and stirred overnight at roomtemperature. The reaction mixture was filtered through Florisil and thefiltrate was concentrated under reduced pressure to afford a yellow oil.The oil was purified by silica gel column chromatography eluted withEtOAc/heptane (10-20% EtOAc) to afford1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxyl-2-methyl-propan-2-ol(12.6 g (86%) as pale yellow liquid.

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-[3-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]pyridine-3-carboxamide(Compound 1890)

N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-(2,6-dimethylphenoxy)pyridine-3-carboxamide(140 mg, 0.32 mmol),143-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-2-ol(215 mg, 0.69 mmol), potassium carbonate (647 μL of 2 M, 1.29 mmol), and1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazole; 3-chloropyridine;dichloropalladium (PEPPSI-IPr) (11 mg, 0.02 mmol) were combined inethanol (3 mL) and the reaction mixture was heated at 80° C. for 21 h.The reaction mixture was cooled to 40° C., glacial AcOH (0.20 mL) wasadded, filtered and the filtrate evaporated under reduced pressure. Theresidue was dissolved in DMSO (3 mL), filtered and purified using areverse phase HPLC-MS method using a Luna C18 (2) column (75×30 mm, 5 μmparticle size) and a dual gradient run from 10-99% mobile phase B over30.0 minutes (mobile phase A=H₂O (5 mM HCl), mobile phase B=CH₃CN) togiveN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-[3-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]pyridine-3-carboxamide(Compound 1890) (HCl salt) (80 mg, 40%) 1H NMR (400 MHz, DMSO-d6) δ12.39 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.66 (t,J=7.9 Hz, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.21-7.14 (m, 4H), 7.14-7.07 (m,1H), 6.84 (dt, J=10.6, 2.3 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.54 (s,2H), 4.61 (s, 1H), 3.61 (s, 2H), 2.07 (s, 1H), 2.06 (s, 6H), 1.19 (s,6H). ESI-MS m/z calc. 580.1792, found 581.2 (M+1)⁺; Retention time: 1.76minutes.

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,6-dimethylphenoxy)-6-[3-fluoro-5-(3-hydroxy-2-methyl-propoxy)phenyl]pyridine-3-carboxamide    (Compound 1797)

PREPARATION 133:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxamide(Compound 2081) (Isomer 1, R or S stereoisomer) (Compound 2039) (Isomer2, R or S stereoisomer) Step 1: Ethyl2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate

To a solution of2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (1.3g, 4.0 mmol) in ethanol (40 mL) was slowly added thionyl chloride (1.0g, 584 μL, 8.0 mmol) and the reaction mixture was stirred at reflux forsix hours. The solvent was evaporated under reduced pressure to giveethyl 2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate(1.3 g, 95%) as a colorless solid.

Step 2: Ethyl6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxylate

A mixture of ethyl2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate (700 mg,1.99 mmol),4,4,5,5-tetramethyl-2-(3,5,5-trimethylcyclopenten-1-yl)-1,3,2-dioxaborolane(517 mg, 2.19 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladiumdichloride (437 mg, 0.60 mmol), and Na₂CO₃ (633 mg, 5.97 mmol) indioxane (9 mL) and water (1 mL) was heated in a sealed vessel at 150° C.for 16 hours. The reaction mixture was filtered, and the solids werewashed with EtOAc. The combined organics were evaporated, and theresidue was purified by silica gel column chromatography using agradient of 100% hexanes to 20% EtOAc in hexanes to afford ethyl6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxylate(97 mg, 11%) as a white solid. ESI-MS m/z calc. 425.23663, found 426.2(M+1)⁺; Retention time: 2.4 minutes.

Step 3:6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxylicacid

To a solution of ethyl6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxylate(92 mg, 0.2 mmol) in THF (520 μL) was added NaOH (650 μL of 1 M, 0.6mmol) and then MeOH (520 μL) and the reaction mixture was heated to 50°C. for 4 hrs. The reaction mixture was neutralized with 1 M HCl (3.0 mL)and extracted with EtOAc (10 mL×2). The combined extracts were driedover Na₂SO₄ and evaporated under reduced pressure to give6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxylicacid (77 mg, 90%) as a light yellow solid. ESI-MS m/z calc. 397.20532,found 398.2 (M+1)⁺; Retention time: 1.92 minutes; 1H NMR (400 MHz, DMSO)δ 13.11 (s, 1H), 7.98 (s, 2H), 7.56 (s, 1H), 7.49 (d, J=9.9 Hz, 1H),6.93 (d, J=10.7 Hz, 1H), 5.67 (s, 1H), 3.85 (d, J=6.6 Hz, 2H), 2.87 (dd,J=14.1, 7.0 Hz, 1H), 2.13-1.98 (m, 2H), 1.46-1.38 (m, 4H), 1.24 (s, 4H),1.08 (d, J=6.9 Hz, 3H), 0.99 (d, J=6.7 Hz, 6H).

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxamide(Compound 2081) (Compound 2039)

6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxylicacid (74 mg, 0.19 mmol) and CDI (45 mg, 0.28 mmol) were mixed in DMF(740 μL) under and atmosphere of nitrogen and the reaction mixture washeated to 45° C. for 45 minutes. In a separate vial,6-aminopyridine-2-sulfonamide (80.62 mg, 0.4655 mmol) and NaH (18 mg,0.46 mmol) were mixed slowly in DMF (370.0 μL) and mixture was heated to45° C. for 45 minutes. The 6-aminopyridine-2-sulfonamide reactionmixture was added to the activated acid and the reaction mixture washeated at 50° C. for 16 h. The reaction mixture was filtered and thenpurified directly by reverse-phase preparative chromatography utilizinga C18 column and HPLC-MS method 10-99% mobile phase B (mobile phaseA=water (de-ionized, no acid modifier), mobile phase B=acetonitrile) toaffordN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxamide(Compound 2081) (Compound 2039) (64 mg, 62%) as an off-white solid ,ESI-MS m/z calc. 552.22064, found 553.4 (M+1)⁺; Retention time: 2.25minutes; 1H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 7.96 (d, J=8.2 Hz, 1H),7.86 (d, J=8.2 Hz, 1H), 7.68-7.60 (m, 1H), 7.56 (s, 1H), 7.49 (d, J=9.6Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.01-6.84 (m, 1H), 6.72 (d, J=8.4 Hz,1H), 6.55 (s, 2H), 5.62 (d, J=1.7 Hz, 1H), 3.85 (d, J=6.6 Hz, 2H), 2.66(ddd, J=14.3, 7.4, 1.8 Hz, 1H), 2.03 (dd, J=13.2, 6.6 Hz, 1H), 1.95 (dd,J=12.1, 7.5 Hz, 1H), 1.38-1.28 (m, 4H), 1.25 (s, 3H), 0.99 (d, J=6.7 Hz,6H), 0.93 (d, J=6.9 Hz, 3H).

Step 5:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxamide(Compound 2081) (Isomer 1, R or S stereoisomer) andN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxamide(Compound 2039) (Isomer 2, R or S stereoisomer)

The stereoisomers were separated using supercritical fluidchromatography on a ChiralCel AD-H (250×10 mm), 5 μm column using 20%EtOH (0.1% TFA) in CO₂ at a flow rate of 10.0 mL/min. The separatedenantiomers were separately concentrated to give the pure compound. SFCPeak 1:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxamide(Compound 2081) (Isomer 1, R or S stereoisomer) ESI-MS m/z calc.552.22064, found 553.2 (M+1)⁺; Retention time: 2.26 minutes. SFC Peak 2N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,5,5-trimethylcyclopenten-1-yl)pyridine-3-carboxamide(Compound 2039) (Isomer 2, R or S stereoisomer) ESI-MS m/z calc.552.22064, found 553.2 (M+1)⁺; Retention time: 2.26 minutes.

PREPARATION 134:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Isomer 1, R or S stereoisomer) (Compound 2374) (Isomer2, R or S stereoisomer) Step 1:6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxylicacid

A mixture of6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,5,5-tetramethylcyclopenten-1-yl)pyridine-3-carboxylicacid (389 mg, 0.94 mmol) (prepared in a similar manner to that describedin preparation 133), palladium hydroxide (80 mg, 0.57 mmol) and ammoniumformate (1.19 g, 18.91 mmol) in ethanol (10 mL) were combined in amicrowave vial and heated to 85° C. for 3 h. The reaction mixture wascooled to room temperature and a further aliquot of ammonium formate(1.19 g, 18.91 mmol) and palladium hydroxide (80 mg, 0.57 mmol) wasadded, and irradiated under microwave conditions at 85° C. for 4 h. Thereaction mixture was filtered over celite, washed with methanol and thefiltrate concentrated under reduced pressure, then diluted with 1N HCland washed with ethyl acetate (2×). The combined organic layers weredried over sodium sulfate, filtered and concentrated under reducedpressure to a clear oil. The oil was purified by silica gel columnchromatography using a gradient from 100% dichloromethane to 20%methanol in dichloromethane followed by 20% methanol in ethyl acetate togive6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxylicacid (52 mg, 13%) as a white solid.

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Compound 2374)

A solution of6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxylicacid (52 mg, 0.13 mmol) and carbonyl diimidazole (31 mg, 0.19 mmol) indimethylformamide (0.5 mL) was stirred at 45° C. for 90 minutes. Aseparate solution of 6-aminopyridine-2-sulfonamide (44 mg, 0.25 mmol)and sodium hydride (10 mg, 0.25 mmol) in dimethylformamide (0.5 mL) wasstirred at 45° C. for 45 minutes was then added to the activated acidand the resulting mixture was stirred at 45° C. for 2 h. The reactionmixture was filtered and purified using a reverse phase HPLC-MS methodusing a Luna C18 (2) column (75×30 mm, 5 μm particle size) and a dualgradient run from 1-99% mobile phase B over 15.0 minutes (mobile phase A=H₂O (5 mM HCl), mobile phase B=acetonitrile) to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Compound 2374) (HCl salt) (51 mg, 67%) as an off-whitesolid. 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 7.91 (dd, J=20.4, 8.2 Hz,2H), 7.66 (t, J=7.9 Hz, 1H), 7.57 (s, 1H), 7.51 (d, J=9.8 Hz, 1H), 7.25(d, J=7.3 Hz, 1H), 6.93 (d, J=10.7 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.51(s, 2H), 3.86 (d, J=6.6 Hz, 2H), 3.58 (dd, J=12.2, 6.5 Hz, 1H), 2.55 (d,J=12.3 Hz, 1H), 2.06 (dt, J=13.2, 6.6 Hz, 1H), 1.63 (dd, J=12.4, 6.4 Hz,1H), 1.50 (d, J=13.0 Hz, 1H), 1.39 (d, J=12.9 Hz, 1H), 1.15 (s, 3H),1.08-0.93 (m, 9H), 0.80 (s, 3H), 0.69 (s, 3H). ESI-MS m/z calc.568.25195, found 569.3 (M+1)⁺; Retention time: 2.4 minutes.

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Isomer 1, R or S stereoisomer) andN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2374) (Isomer 2, R or S stereoisomer)

The stereoisomers were separated using supercritical fluidchromatography on a Chiralpak IC (250×10 mm), 5 μm column using 17% EtOH(DeNat)+0.1% TFA in CO₂ at a flow rate of 10.0 mL/min. The separatedenantiomers were separately concentrated to give the pure compound. SFCPeak 1:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Compound 2374) ESI-MS m/z calc. 568.25195, found 569.3(M+1)⁺; Retention time: 2.4 minutes. 1H NMR (400 MHz, MeOD) δ 7.87 (d,J=8.2 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.70 (dd, J=8.3, 7.4 Hz, 1H),7.54 (s, 1H), 7.46-7.38 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.75 (dt,J=10.5, 2.3 Hz, 1H), 3.82 (d, J=6.5 Hz, 2H), 3.67 (dd, J=12.3, 6.4 Hz,1H), 2.66 (t, J=12.5 Hz, 1H), 2.11 (dt, J=13.3, 6.7 Hz, 1H), 1.69 (dd,J=12.6, 6.3 Hz, 1H), 1.49 (dd, J=38.8, 13.1 Hz, 2H), 1.18 (d, J=5.6 Hz,3H), 1.10-1.00 (m, 9H), 0.81 (s, 3H), 0.75 (s, 3H). SFC Peak 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylcyclopentyl)pyridine-3-carboxamide(Compound 2492) (Compound 2374). ESI-MS m/z calc. 568.25195, found 569.3(M+1)⁺; Retention time: 2.4 minutes. 1H NMR (400 MHz, MeOD) δ 7.87 (d,J=8.2 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.70 (dd, J=8.3, 7.4 Hz, 1H),7.54 (s, 1H), 7.46-7.38 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.75 (dt,J=10.5, 2.3 Hz, 1H), 3.82 (d, J=6.5 Hz, 2H), 3.67 (dd, J=12.3, 6.4 Hz,1H), 2.66 (t, J=12.5 Hz, 1H), 2.11 (dt, J=13.3, 6.7 Hz, 1H), 1.69 (dd,J=12.6, 6.3 Hz, 1H), 1.49 (dd, J=38.8, 13.1 Hz, 2H), 1.18 (d, J=5.6 Hz,3H), 1.10-1.00 (m, 9H), 0.81 (s, 3H), 0.75 (s, 3H).

PREPARATION 135:6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-N-[[6-(pent-4-ynoylamino)-2-pyridyl]sulfonyl]pyridine-3-carboxamide(Compound 2540) Step 1:N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-

N-[(6-amino-2-pyridyl)sulfonyl[-2,6-dichloro-pyridine-3-carboxamide (2.0g, 5.8 mmol) and (2R,5S)-2,5-dimethylpyrrolidine (0.7 g, 7.2 mmol) inDMSO (10 mL) was treated with K₂CO₃ (2.4 g, 17 mmol) and heated at 120°C. under stirring for 3 h. The reaction mixture was cooled down andcarefully added to cold mixture of HCl (2.881 mL of 12 M, 35 mmol) andwater (50 mL) forming a white foam. The reaction mixture was allowed tostir at room temperature for 30 min, filtered and the white solid wastriturated with IPA (100mL) to give the desired compound.

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 773)

N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide(62 mg, 0.15 mmol), (4-chloro-3-propoxy-phenyl)boronic acid (48 mg, 0.23mmol), tetrakis(triphenylphosphine)palladium (0) (10 mg, 0.009 mmol),potassium carbonate (300 μL, 2 M, 0.40 mmol) and DMF (1.7 mL) wereheated at 100° C. overnight. The reaction mixture was filtered andpurified by reverse phase HPLC utilizing a gradient of 1-99%acetonitrile in 5 mM aq HCl. ESI-MS m/z 544.3 (M₊1)⁺; Retention time:1.7 minutes; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 7.83 (d, J=1.9Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.70-7.61 (m, 2H), 7.52 (d, J=8.3 Hz,1H), 7.37 (d, J=7.9 Hz, 1H), 7.23 (dd, J=7.3, 0.8 Hz, 1H), 6.72 (d, 1H),6.48 (s, 2H), 4.13 (t, J=6.5 Hz, 2H), 4.09-3.97 (m, 2H), 2.05-1.91 (m,2H), 1.81 (h, J=7.2 Hz, 2H), 1.74-1.61 (m, 2H), 1.10 (d, J=6.2 Hz, 6H),1.03 (t, J=7.4 Hz, 3H).

Step 3:6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-N-[[6-(pent-4-ynoylamino)-2-pyridyl]sulfonyl]pyridine-3-carboxamide(Compound 2540)

N-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 773) (10 mg, 0.02 mmol) in DCM (2 mL) at 0° C. was addedtriethylamine (11 mg, 15 μL, 0.11 mmol) and pent-4-ynoyl chloride (4 mg,0.04 mmol). The reaction mixture was then stirred at 0° C. for 5minutes, then at rt for 2 h. The reaction mixture was evaporated underreduced pressure and the crude mixture was purified by reverse phaseHPLC using 10-100% ACN in Water (TFA modifier). The salt was neutralizedwith SPE-CO_(S)H cartridge, eluted with MeOH/DCM to give the desiredcompound. ESI-MS m/z 624.3 (M+1)⁺; Retention time: 0.9 minutes; 1H NMR(300 MHz, CDCl₃) 6 8.73 (d, J=8.2 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.04(t, J=7.9 Hz, 1H), 7.98-7.89 (m, 2H), 7.56 (dd, J=8.2, 1.9 Hz, 1H), 7.51(d, J=2.4 Hz, 2H), 4.21 (d, J=6.1 Hz, 2H), 4.10 (t, J=6.4 Hz, 2H), 2.73(t, J=6.9 Hz, 2H), 2.64-2.47 (m, 4H), 2.11 (d, J=2.8 Hz, 2H), 2.00-1.85(m, 4H), 1.34 (d, J=6.6 Hz, 6H), 1.25 (s, 6H), 1.11 (t, J=7.4 Hz, 5H),0.93-0.79 (m, 3H).

PREPARATION 136:N-[4-[3-(4-chlorophenyepropyl]piperazin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2141) Step 1:2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxylic acid

A mixture of 2-fluoropyridine-3-carboxylic acid (71 mg, 0.5 mmol),(4S)-2,2,4-trimethylpyrrolidine (HCl salt) (150 mg, 1.0 mmol), potassiumcarbonate (207 mg, 1.5 mmol), and cesium fluoride (152 mg, 1.0 mmol) inDMSO (500 μL) was stirred at 130° C. for six hours. The reaction mixturewas diluted with water, adjusted to pH 4 with 1 M HCl, and extractedwith ethyl acetate. The combined extracts were washed with brine, driedover sodium sulfate, and evaporated under reduced pressure. The residuewas purified using reverse phase HPLC-MS using a Luna C18 (2) column(75×30 mm, 5 μm particle size) and a dual gradient run from 1-70% mobilephase B over 15.0 minutes (mobile phase A=H₂O (5 mM HCl). mobile phaseB=CH₃CN) to give the desired compound.

Step 2:benzyl4-[[2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carbonyl]sulfamoyl]piperazine-1-carboxylate

A solution of (S)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinic acid (117mg, 0.5 mmol) and chlorosulfonyl isocyanate (85 mg, 52 μL, 0.6 mmol) indichloromethane (3 mL) was stirred for 30 minutes, and was slowly addedto a solution of benzyl piperazine-1-carboxylate (110 mg, 96 μL, 0.5mmol) and pyridine (59 mg, 60 μL, 0.8 mmol) in dichloromethane (2 mL).The reaction mixture was stirred for two hours, evaporated under reducedpressure and purified by silica gel column chromatography with 0-5%methanol in dichloromethane as eluent to give benzyl(S)-4-(N-(2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinoyl)sulfamoyl)piperazine-1-carboxylate(35 mg, 13%) as a colorless oil. ESI-MS m/z 516.6 (M+1)⁺; Retentiontime: 1.65 minutes.

Step 3:N-piperazin-1-ylsulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

A mixture of benzyl(S)-4-(N-(2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinoyl)sulfamoyl)piperazine-1-carboxylate(0.22 g, 0.43 mmol) and palladium on carbon (20 mg, 0.02 mmol) inmethanol (2 mL) was stirred under a hydrogen atmosphere for 16 hours.The reaction mixture was filtered and evaporated to give(S)—N-(piperazin-1-ylsulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide(0.13 g, 80%) as a colorless solid.

Step 4:N-[4-[3-(4-chlorophenyepropyl]piperazin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2141)

A solution of(S)-N-(piperazin-1-ylsulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide(30 mg, 0.08 mmol) and 3-(4-chlorophenyl)propanal (14 mg, 0.08 mmol) in1,2-dichloroethane (800 tL) was stirred for five minutes, and sodiumtriacetoxyborohydride (33 mg, 0.16 mmol) was added. The reaction mixturewas stirred for 16 hours, diluted with methanol, filtered, and purifiedusing a reverse phase HPLC-MS method using a Luna C18 (2) column (75×30mm, 5 μm particle size) and a dual gradient run from 1-99% mobile phaseB over 15.0 minutes (mobile phase A=H₂O (5 mM HCl), mobile phaseB=CH₃CN) to give the desired compound. ESI-MS m/z 534.6 (M+1)⁺;Retention time: 1.23 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(3R)-3-[(4-tert-butoxyphenyl)methylamino]pyrrolidin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2698),-   N-[[3-[(4-tert-butoxyphenyl)methylamino]-1-piperidyl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2697),-   N-[(3R)-3-[[4-fluoro-3-(trifluoromethoxy)phenyl]methylamino]pyrrolidin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2681),-   N-[(3R)-3-[3-(4-chlorophenyl)propylamino]pyrrolidin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2717) and-   N-[(3R)-3-[(2,4-dichlorophenyl)methylamino]pyrrolidin-1-yl]sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2693)

PREPARATION 137:6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-piperidylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2655) Step 1:6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxylicacid

A mixture of2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (1.5g, 3.6 mmol), (4S)-2,2,4-trimethylpyrrolidine (HCl salt) (0.8 g, 5.8mmol), K₂CO₃ (1.6 g, 11.6 mmol), and CsF (1.1 g, 7.5 mmol) in DMSO (5mL) was stirred at 130° C. for two days. The reaction mixture wasdiluted with water, adjusted to pH 4 with 1 M HCl, and extracted withethyl acetate. The combined extracts were washed with brine, dried oversodium sulfate, and evaporated under reduced pressure. The residue waspurified by silica gel chromatography with 0-6% methanol indichloromethane to give6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxylicacid (1.2 g, 82%) as a tan foam. ESI-MS m/z calc. 400.21622, found 401.0(M+1)⁺; Retention time: 1.92 minutes (3 min).

Step 2:6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

A solution of6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxylicacid (120 mg, 0.3 mmol) and CDI (73 mg, 0.5 mmol) in DMF (1.5 mL) wasstirred at 45° C. for 30 minutes, and ammonium hydroxide (525 μL of30%w/v, 4.5 mmol) was added. The reaction mixture was stirred at 45° C.for three days, diluted with water, and extracted with ethyl acetate.The combined extracts were washed with brine, dried over sodium sulfate,and evaporated under reduced pressure. The residue was purified bysilica gel column chromatography with 0-5% methanol in dichloromethaneto give6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(82 mg, 68%). ESI-MS m/z 400.5 (M+H)⁺; Retention time: 1.78 minutes (3min).

Step 3:6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-piperidylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2655)

A solution of6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(32 mg, 0.1 mmol) and NaH (5 mg, 0.1 mmol) in DMF (800 μL) was stirredfor 30 minutes, and benzyl 3-chlorosulfonylpiperidine-1-carboxylate (51mg, 0.2 mmol) was added. The reaction mixture was stirred for 16 hours.The reaction was filtered and purified using a reverse phase HPLC-MSmethod using a Luna C18 (2) column (75×30 mm, 5 μm particle size) and adual gradient run from 1-99% mobile phase B over 15.0 minutes (mobilephase A =H₂O (5 mM HCl), mobile phase B=CH₃CN). The intermediate andpalladium (10 mg, 0.01 mmol) (10% on carbon) in MeOH was stirred under ahydrogen atmosphere for 17 hours. The reaction was filtered and purifiedusing a reverse phase HPLC-MS method using a Luna C18 (2) column (75×30mm, 5 μm particle size) and a dual gradient run from 1-99% mobile phaseB over 15.0 minutes (mobile phase A=H₂O (5 mM HCl), mobile phaseB=CH₃CN) to give the desired compound. ESI-MS m/z 547.6 (M+1)⁺;Retention time: 1.65 minutes (3 min)

The following compounds can be synthesized using the proceduresdescribed herein:

-   6-(3-fluoro-5-isobutoxy-phenyl)-N-pyrrolidin-3-ylsulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2042),-   N-cyclopentylsulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2113),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[[(3R)-3-piperidyl]sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2677),-   6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-pyridylsulfamoyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1448) and-   6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-methoxy-3-pyridyl)sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1359).

PREPARATION 138:N-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2473)

(3-fluoro-5-isobutoxy-phenyl)boronic acid (5 mg, 0.02 mmol),N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(10 mg, 0.02 mmol), 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazole;3-chloropyridine; dichloropalladium (3 mg, 0.005 mmol) and K₂CO₃ (3 mg,0.02 mmol) were combined in N-propanol (0.5 mL). The reaction mixturewas heated to 90° C. for 16 h under an atmosphere of nitrogen. Thereaction mixture was filtered and purified by reverse phase HPLC using1-99% ACN in water (0.05% HCl modifier) over 15 minutes to give thedesired compound as a pale solid. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s,1H), 7.73 (d, J=11.2 Hz, 1H), 7.36 (s, 1H), 7.24 (dd, J=15.0, 8.6 Hz,2H), 6.96 (dt, J=10.9, 2.5 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.53 (s,1H), 3.82 (d, J=6.6 Hz, 2H), 2.59 (p, J=10.2 Hz, 2H), 2.22 (s, 1H),2.07-1.98 (m, 1H), 1.87 (dd, J=12.0, 5.7 Hz, 1H), 1.54 (d, J=6.6 Hz,6H), 1.41 (t, J=12.1 Hz, 1H), 0.98 (d, J=6.7 Hz, 6H), 0.87 (d, J=6.3 Hz,3H).1H NMR (400 MHz, DMSO-d6) 5 12.62 (s, 1H), 7.73 (d, J=11.2 Hz, 1H),7.36 (s, 1H), 7.24 (dd, J=15.0, 8.6 Hz, 2H), 6.96 (dt, J=10.9, 2.5 Hz,1H), 6.70 (d, J=8.3 Hz, 1H), 6.53 (s, 1H), 3.82 (d, J=6.6 Hz, 2H), 2.59(p, J=10.2 Hz, 2H), 2.22 (s, 1H), 2.07-1.98 (m, 1H), 1.87 (dd, J=12.0,5.7 Hz, 1H), 1.54 (d, J=6.6 Hz, 6H), 1.41 (t, J=12.1 Hz, 1H), 0.98 (d,J=6.7 Hz, 6H), 0.87 (d, J=6.3 Hz, 3H).

PREPARATION 139:N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2477) Step 1:6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxylicacid

A mixture of2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (227mg, 0.7 mmol), 2-phenylpyrrolidine (206 mg, 1.4 mmol), CsF (213 mg, 1.4mmol), and K₂CO₃ (194 mg, 1.4 mmol) in DMSO (3.5 mL) was stirred at 120°C. for 16 hours. The reaction mixture was diluted with water, adjustedto pH 4 with 1 M HCl, and extracted with ethyl acetate (2×). Thecombined extracts were washed with brine, dried over sodium sulfate, andevaporated under reduced pressure. The residue was purified by silicagel column chromatography with 0-5% methanol in dichloromethane to give6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxylicacid (190 mg, 62%). ESI-MS m/z 435.5 (M₊1)⁺; Retention time: 0.9 minutes(3 min).

Step 2:N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2477)

A solution of6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxylicacid (43 mg, 0.1 mmol) and chlorosulfonyl isocyanate (11 uL, 0.1 mmol)in dichloromethane was stirred for 30 minutes, and tent-butylN-[(3R)-pyrrolidin-3-yl]carbamate (27 mg, 0.2 mmol) and triethylamine(21 uL, 0.2 mmol) were added. The reaction mixture was stirred for 16hours, and HCl (4M in dioxane) (200 uL, 0.8 mmol) was added. Afterstirring for four hours, the sovent was removed under reduced pressure,and the residue was purified using a reverse phase HPLC-MS method usinga Luna C18 (2) column (75×30 mm, 5μm particle size) and a dual gradientrun from 1-99% mobile phase B over 15.0 minutes (mobile phase A=H₂O (5mM HCl), mobile phase B=CH₃CN) to giveN-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide(Compound 2477) (9 mg, 16%). ESI-MS m/z 582.6 (M₊1)⁺; Retention time:1.82 minutes (3 min).

The following compound can be synthesized using the procedures describedherein:

-   N-[(3R)-3-aminopyrrolidin-1-yl]sulfonyl-2-(2-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2325)

PREPARATION 140: 3-(cyclopropylmethyl)-2,2-dimethyl-pyrrolidine Step 1:1-benzyl-3-(cyclopropylmethyl)pyrrolidin-2-one

1-Benzylpyrrolidin-2-one (5.0 g, 28.6 mmol) was dissolved in THF (100mL) and cooled to −78° C. n-BuLi (2.5M, 13.7 mL, 34.3 mmol) was addeddropwise at −78° C. and the reaction mixture was stirred at −78° C. for30 minutes. (Bromo-methyl)cyclopropane (4.6 g, 34.3 mmol) was added andstirring continued at −78° C. for 30 minutes. The reaction mixture wasallowed to reach RT slowly overnight. The mixture was quenched with sat.aq. NH₄Cl and extracted with EtOAc (2×). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(heptanes/EtOAc 2:1) affording1-benzyl-3-(cyclopropylmethyl)-pyrrolidin-2-one (3.9 g, 60%) as acolorless oil. 1H NMR (CDCl₃, 300 MHz): 0.05 (m, 2H); 0.43 (m, 2H); 0.74(m,1H); 1.22 (m, 1H); 1.68 (m, 1H); 1.76 (m, 1H); 2.21 (m, 1H); 2.55 (m,1H); 3.08 (m, 2H); 4.43 (q, 2H); 7.24 (m, 5H).

Step 2: 1-benzyl-3-(cyclopropylmethyl)-2,2-dimethyl-pyrrolidine

ZrCl₄ (3.96 g, 17.0 mmol) was added to THF (100 mL) at −10° C. and thereaction mixture was stirred for 30 minutes.1-Benzyl-3-(cyclopropylmethyl)pyrrolidin-2-one (3.95 g, 17.0 mmol) wasadded as a solution in THF (10 mL). The reaction mixture was stirred for10 minutes, then MeMgBr (3.0 M, 34 mL, 102 mmol) was added dropwise at0° C. The reaction mixture was allowed to reach RT overnight. It wasquenched at 0° C. with 30% aq. NaOH (20 mL) and stirred for 10 min.Water (100 mL) was added and the reaction mixture was extracted withCH₂Cl₂ (2×). The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (heptanes/EtOAc 4:1)affording 1-benzyl-3-(cyclopropylmethyl)-2,2-dimethylpyrrolidine (2.0 g,48%) as a colorless oil. 1H NMR (CDCl₃, 300 MHz): −0.03 (m, 1H); 0.07(m, 1H); 0.42 (m, 2H); 0.66 (m, 1H); 0.76 (s, 3H); 1.12 (s, 3H); 1.19(m, 2H); 1.39 (m, 1H); 1.90 (m, 1H); 2.03 (m, 1H); 2.32 (m, 1H); 2.85(m, 1H); 3.20 (d, 1H); 3.87 (d, 1H); 7.25 (m, 5H).

Step 3: 3-(cyclopropylmethyl)-2,2-dimethyl-pyrrolidine

1-Benzyl-3-(cyclopropylmethyl)-2,2-dimethylpyrrolidine (2.0 g, 8.2 mmol)was dissolved in MeOH (100 mL) and conc. HCl (5 mL) was added. Pd/C (400mg) was added and the reaction mixture was stirred over the weekendunder 5 bars of H₂. The reaction mixture was filtered over Celite andconcentrated under reduced pressure affording3-(cyclopropylmethyl)-2,2-dimethyl-pyrrolidine hydrochloride (1.3 g,84%) as an off-white solid. 1H NMR (CD₃OD, 300 MHz): 0.07 (m, 1H); 0.13(m, 1H); 0.47 (m, 2H); 0.72 (m, 1H); 1.17 (s, 3H); 1.19 (m, 1H); 1.34(m, 1H); 1.43 (s, 3H); 1.83 (m, 1H); 2.01 (m, 1H); 2.38 (m, 1H); 3.26(m, 2H). ESI-MS m/z calc. 153.15175, found 154.0 (M+1)⁺.

PREPARATION 141:N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideStep 1:N-(benzenesulfonyl)-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide

To a solution of the2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (10.0g, 30.89 mmol) in DMF (30.0 mL) at ambient temperature in a round bottomflask was slowly added carbonyldiimidazole (5.510 g, 33.98 mmol)portionwise and the mixture stirred for 100 min. Meanwhile tobenzenesulfonamide (6.069 g, 38.61 mmol) in DMF (30.0 mL) (homogenoussolution) in another round bottom flask was added NaHMDS in THF (38.61mL of 1.0 M, 38.61 mmol) portionwise via syringe over 30-45 min and oncompletion of addition the mixture was stirred a further 30 min. Themixture containing the activated acid was then added to the mixturecontaining the deprotonated sulfonamide and the combined mixture wasstirred 1 h. The reaction was cooled with a 0° C. bath and quenched byaddition of 12N aqueous HCl (11.58 mL) in portions over 2-3 minutesresulting in precipitated solids. Transferred the reaction mixture to aseparatory funnel and ethyl acetate (100.0 mL) was added. Added 1Naqueous HCl (20.0 mL) giving a pH=2-3 then separated the layers andwashed the organic layer with 5:1 water/saturated aqueous brine (120.0mL), saturated aqueous brine (1×50mL, 1×30 mL), dried (sodium sulfate),filtered and concentrated under reduced pressure to a clear light yellowoil that was concentrated from isopropanol several more times resultingin precipitation of a solid. The solid was slurried overnight inisopropanol then filtered and washed the solid with heptane (50 mL) anddried in vacuo givingN-(benzenesulfonyl)-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(10.22 g, 22.08 mmol, 71.47%) as a white solid. ¹H NMR (400 MHz, DMSO) δ12.85 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.02 (dd,J=5.3, 3.3 Hz, 2H), 7.76 (d, J=7.4 Hz, 1H), 7.69 (t, J=7.6 Hz, 2H),7.51-7.43 (m, 2H), 6.99 (dd, J=10.8, 2.3 Hz, 1H), 3.85 (d, J=6.5 Hz,2H), 2.04 (dt, J=13.3, 6.6 Hz, 1H), 1.00 (d, J=6.7 Hz, 6H). ESI-MS m/zcalc. 462.08163, found 463.19 (M+1)⁺; Retention time: 2.93 minutes [5minute method].

Step 2:N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

To a round bottom flask outfitted with a reflux condenser was addedN-(benzenesulfonyl)-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(10.0 g, 21.60 mmol) and NMP (40 mL) and stirring was commenced. Warmedto 50° C. and began portionwise addition of potassium carbonate (5.970g, 43.20 mmol) followed by (4S)-2,2,4-trimethylpyrrolidine (4.890 g,43.20 mmol) in one portion. After stirring for 10 min, heated themixture to 125° C. for 65 h, then cooled to 10° C. and added 1N aqueousHCl (50.0 mL, 50.00 mmol) in portions to give pH 1-2 and a precipitatedsolid. Added ethyl acetate (100.0 mL) to dissolve solid and diluted theaqueous layer with water (50.0 mL) and stirred for 10 min. The mixturewas transferred to a separatory funnel and layers were allowed toseparate. Added aqueous 1N HCl dropwise until all solids were dissolved.Separated the layers and the aqueous layer was back extracted with ethylacetate (50.00 mL) followed by combination of the organic layers. To thecombined organic layers was added water (50.00 mL) giving an emulsionwhich was clarified by the addition of 1N aqueous HCl (25.00 mL).Separated the layers then the organic layer was washed with saturatedaqueous brine (50.00 mL), dried over Na₂SO₄, filtered through celite andrinsed with ethyl acetate (30.00 mL). The filtrate was concentratedunder reduced pressure and the residue was purified by silica gelchromatography using a gradient from 100% hexanes to 50% EtOAc giving alight amber oil which was evaporated from isopropanol several timesunder reduced pressure providingN-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(9.73 g, 18.03 mmol, 83.5%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6)δ 12.57 (s, 1H), 8.16-7.88 (m, 2H), 7.82-7.57 (m, 4H), 7.47 (t, J=1.8Hz, 1H), 7.40 (dt, J=9.9, 2.0 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 6.89 (dt,J=10.8, 2.3 Hz, 1H), 3.83 (d, J=6.6 Hz, 2H), 2.48-2.28 (m, 2H), 2.07(dtt, J=26.6, 13.4, 6.4 Hz, 2H), 1.83 (dd, J=11.9, 5.5 Hz, 1H), 1.57 (d,J=17.3 Hz, 6H), 1.38 (t, J=12.1 Hz, 1H), 1.04 (d, J=6.1 Hz, 1H), 0.98(d, J=6.7 Hz, 6H), 0.66 (d, J=6.3 Hz, 3H). ESI-MS m/z calc. 539.2254,found 540.0 (M+1)⁺; Retention time: 3.25 minutes [5 minute method].

PREPARATION 142:N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideStep 1: Ethyl 2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxylate

Ethyl 2,6-dichloropyridine-3-carboxylate (7.00 g, 31.81 mmol) and(6-isopropoxy-3-pyridyl)boronic acid (5.04 g, 27.85 mmol) were combinedand dissolved in ethanol (50.40 mL) and toluene (50.40 mL). A suspensionof sodium carbonate (10.12 g, 95.47 mmol) in water (10.08 mL) was added.Under nitrogen, tetrakis(triphenylphosphine)palladium (1.103 g, 0.9547mmol) was added. The reaction mixture was allowed to warm to 80° C. andstirred for 2 h. The volatiles were removed under reduced pressure. Theremaining solids were partitioned between water (75 mL) and ethylacetate (75 mL). The organic layer was washed with saturated aqueoussodium chloride solution (1×75 mL), dried over sodium sulfate, filteredand concentrated under reduced pressure. The material was subjected tosilica gel column chromatography using a gradient from 100% hexanes to5% ethyl acetate in hexanes. Ethyl2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxylate (3.95 g, 12.07mmol, 43.33%) was obtained as a clear colorless oil. ¹H NMR (400 MHz,DMSO) δ 8.91 (s, 1H), 8.37 (dd, J=8.7, 2.3 Hz, 1H), 8.30 (d, J=8.1 Hz,1H), 8.10 (d, J=8.1 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.34 (dt, J=12.3,6.1 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.51 (d, J=1.7 Hz, 1H), 1.42-1.30(m, 9H). ESI-MS m/z calc. 320.09277, found 321.2 (M+1)⁺; Retention time:0.72 minutes.

Step 2: 2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxylic acid

A solution of sodium hydroxide (2.594 g, 64.85 mmol) in water (20.80 mL)was added to a solution of ethyl2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxylate (4.16 g, 12.97mmol) in isopropanol (20.8 mL) stirring at 90° C. The reaction mixturewas stirred at 90° C. for 30 min. After cooling to room temperature, thereaction mixture was diluted with ethyl acetate (75 mL) and extractedwith saturated aqueous sodium bicarbonate (1×75 mL) and aqueous NaOH (1N, 5×50 mL). The aqueous layers were combined and acidified to pH=1 withthe addition of aqueous 6 N HCl. The white precipitate that formed wascollected by vacuum filtration and rinsed with aqueous 1 N HCl toprovide 2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxylic acid(4.2446 g, 12.89 mmol, 99.43%) as a white solid. ESI-MS m/z calc.292.06146, found 293.1 (M+1)⁺; Retention time: 0.59 minutes.

Step 3: 2-aminopyridine-3-sulfonamide

Ammonium hydroxide (590.3 mL of 28% w/v, 4.716 mol) was stirred andcooled in an ice bath. 2-chloropyridine-3-sulfonyl chloride (50 g, 235.8mmol) was dissolved in dichloromethane (150 mL) and added dropwise tothe stirred ammonia solution to maintain a temperature between 5-12° C.On completion of addition, the mixture was stirred 1 h. Stirring washalted and the resulting layers were separated. Concentrated the aqueouslayer under vacuum to remove ammonia resulting in a white solidprecipitate which was collected by filtration and washed with water. Thematerial was dissolved in ammonium hydroxide (236.1 mL of 28% w/v, 1.886mol) and heated in a pressure vessel at 100° C. overnight then reactiontemperature was increased to 150° C. and stirred overnight. The mixturewas cooled to room temperature resulting in a precipitate thenconcentrated under vacuum to remove ammonia resulting in a white solidprecipitate which was collected by filtration and washed with methyltert-butyl ether (100 mL) to give 2-aminopyridine-3-sulfonamide (25.73g, 148.6 mmol, 63.00%) ESI-MS m/z calc. 173.0259, found 174.0 (M+1)⁺.

Step 4:N-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide

To a solution of 2-aminopyridine-3-sulfonamide (4.068 g, 23.49 mmol) inDMF (38.50 mL) (homogenous solution) in a round bottom flask was addedNaH (939.5 mg, 23.49 mmol) portionwise giving an off-white thick slurryand a slight exotherm from 20° C. to 32° C. during addition. The mixturewas stirred at ambient temperature for 30 min. Meanwhile, to a solutionof 2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxylic acid (5.5 g,18.79 mmol) in DMF (38.50 mL) at ambient temperature in another roundbottom flask was slowly added carbonyldiimidazole (3.352 g, 20.67 mmol)portionwise and the mixture stirred for 20 min over which time it becamea light yellow homogenous solution which was then added to the reactionmixture containing the deprotonated sulfonamide. During the addition themixture stayed homogenous with a slight exotherm to 31° C. The combinedmixture was stirred at ambient temperature affording a dark orangehomogenous mixture and after 5 min was slowly added to chilled HCl(93.95 mL of 1 M, 93.95 mmol) (slightly exothermic) giving a pH of 1.The mixture afforded a precipitate and the slurry was stirred for 60 minat ambient temperature. The mixture was then filtered and the solid waswashed three times with 50 mL of water. The solid was then washed threetimes with 50 mL of isopropanol giving an off-white solid that was airdried for 1 h. The solid was next slurried in 50 mL of isopropanol andthe precipitate was filtered and washed three times with 5 mL ofisopropanol. The off-white solid obtained was air dried for 2 h, then invacuo at 45° C. for 48 h givingN-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(8.0 g, 17.86 mmol, 95.06%) ¹H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J=2.5Hz, 1H), 8.33 (dd, J=8.7, 2.6 Hz, 1H), 8.24 (dd, J=5.1, 1.8 Hz, 1H),8.13-8.00 (m, 3H), 6.96 (s, 2H), 6.88 (d, J=8.7 Hz, 1H), 6.83 (dd,J=7.8, 5.0 Hz, 1H), 5.33 (hept, J=6.3 Hz, 1H), 1.32 (d, J=6.2 Hz, 6H).ESI-MS m/z calc. 447.0768, found 448.18 (M+1)⁺; Retention time: 1.55minutes.

Step 5:N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

A vial equipped with magnetic stir bar was charged withN-[(2-amino-3-pyridyl)sulfonyl]-2-chloro-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide(147.8 mg, 0.330 mmol), (4S)-2,2,4-trimethylpyrrolidine (74.71 mg, 0.660mmol) and potassium carbonate (228.0 mg, 1.65 mmol) in DMSO (739 μL).The vial was sealed and stirred at 120° C. for 16 hours then at 140° C.for 30 hours. The reaction mixture was cooled, diluted with minimal DMSOand methanol and filtered. The filtrate was purified directly using areverse phase HPLC-MS method using a Luna C18 (2) column (75×30 mm, 5 μmparticle size) sold by Phenomenex (pn: 00C-4252-U0-AX), and a dualgradient run from 1-99% mobile phase B over 15.0 minutes (mobile phaseA=H₂O (5 mM HCl), mobile phase B=CH₃CN, flow rate=50 mL/min, injectionvolume=950 μL and column temperature=25° C.) givingN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(25.2 mg, 0.048 mmol, 14.6%). ¹H NMR (400 MHz, DMSO) δ 12.49 (s, 1H),8.84 (d, J=2.4 Hz, 1H), 8.31-8.27 (m, 1H), 8.25 (dd, J=7.4, 4.4 Hz, 1H),8.03 (dd, J=7.9, 1.7 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz,1H), 6.86 (d, J=8.7 Hz, 1H), 6.77 (dd, J=7.8, 4.8 Hz, 1H), 6.69 (s, 2H),5.37-5.26 (m, 1H), 2.52 (s, 1H), 2.14 (s, 1H), 1.85 (dd, J=11.9, 5.5 Hz,1H), 1.58 (d, J=10.7 Hz, 6H), 1.39 (t, J=12.1 Hz, 1H), 1.31 (d, J=6.2Hz, 6H), 1.26 (d, J=13.3 Hz, 1H), 0.86 (t, J=6.9 Hz, 1H), 0.76 (d, J=6.3Hz, 3H). ESI-MS m/z calc. 524.2206, found 525.3 (M₊1)⁺; Retention time:1.38 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(2-amino-6-methoxy-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2692),-   N-[(2-amino-3-pyridyl)sulfonyl]-2-[(4S)-3,3-dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 1543) and-   N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-[6-[1,2,2,2-tetradeuterio-1-(trideuteriomethyeethoxy]-3-pyridyl]pyridine-3-carboxamide    (Compound 2714)

PREPARATION 143:6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[[6-(1-piperidyl)-2-pyridyl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 484) Step 1: 6-(1-piperidyl)pyridine-2-sulfonamide

To 6-fluoro-2-pyridinesulfonamide (215 mg, 1.220 mmol) was addedpiperidine (312 mg, 362 3.66 mmol) and the reaction mixture was heatedat 90° C. for 2.5 hours. The reaction mixture was cooled and resultingsolid was dried.1 H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, J=8.8, 7.2 Hz,1H), 7.03 (d, J=7.2 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 2.75 (d, J=5.5 Hz,3H), 1.61 (p, J=3.4, 2.9 Hz, 2H), 1.54 (dd, J=7.0, 3.9 Hz, 3H), 1.49 (s,4H). ESI-MS m/z found 242.2 (M+1)⁺; Retention time: 0.45 minutes.

Step 2:2-chloro-6-(3-(neopentyloxy)-1H-pyrazol-1-yl)-N-((6-(piperidin-1-yl)pyridin-2-yl)sulfonyl)nicotinamide

To 2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylicacid (100 mg, 0.323 mmol) in DMF (0.6 mL) at room temperature was addedcarbonyl diimidazole (78.5 mg, 0.484 mmol) and the reaction mixture wasstirred for 40 minutes. Separately 6-(1-piperidyl)pyridine-2-sulfonamide(93.5 mg, 0.387 mmol) in DMF (0.6 mL) was cooled to 0° C. and treatedwith sodium hydride (15.5 mg, 0.387 mmol) and stirred for 10 min andthen at room temperature for 30 min. The reaction mixtures were thencombined and stirred at room temperature for 30 min. The reactionmixture was cooled to 0° C. and acetic acid (194 mg, 184 μL, 3.23 mmol)was added followed by HCL (269 μL of 6 M, 1.61 mmol) and the reactionmixture was diluted with EtOAc (5 mL) and the layers were separated. Theorganics were dried and concentrated under reduced pressure to give aresidue which was purified by silica gel column chromatography andeluted with 0-14% MeOH-DCM to give2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[[6-(1-piperidyl)-2-pyridyl]sulfonyl]pyridine-3-carboxamide(158 mg, 82%) ESI-MS m/z found 533.2 (M+1)⁺; Retention time: 0.89minutes (1 min); 1H NMR (400 MHz, DMSO-d6) δ 8.44-8.38 (m, 1H), 8.05 (d,J=8.3 Hz, 1H), 7.95 (s, 1H), 7.79-7.70 (m, 2H), 7.23 (d, J=7.2 Hz, 1H),7.12 (d, J=8.7 Hz, 1H), 6.22 (t, J=2.5 Hz, 1H), 3.93 (d, J=1.2 Hz, 2H),3.59 (t, J=5.4 Hz, 3H), 1.66-1.58 (m, 2H), 1.53 (td, J=10.2, 4.8 Hz,3H), 1.00 (s, 9H).

Step 3:6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[6-(1-piperidyl)-2-pyridyl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 484)

A mixture of2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[[6-(1-piperidyl)-2-pyridyl]sulfonyl]pyridine-3-carboxamide(140 mg, 0.223 mmol), potassium carbonate (185 mg, 1.34 mmol) and(4S)-2,2,4-trimethylpyrrolidine (HCl salt) (75 mg, 0.501 mmol) in DMSO(744 μL) was heated at 150° C. for 5 h. The reaction mixture was cooled,diluted with EtOAc and the aqueous and organic layers were separated.The organics were washed with brine, dried, concentrated under reducedpressure and the resulting residue was purified by silica gel columnchromatography eluting with 0-15% MeOH-DCM to give6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[[6-(1-piperidyl)-2-pyridyl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 484) (38 mg, 28%). ESI-MS m/z calc 609.31, found 610.1 (M+1)⁺;retention time 2.1 min (3 min run); 1H NMR (400 MHz, Methanol-d4) δ 8.25(d, J=2.8 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.69 (dd, J=8.7, 7.2 Hz, 1H),7.31 (d, J=7.2 Hz, 1H), 6.98 (dd, J=8.5, 6.5 Hz, 2H), 5.99 (d, J=2.8 Hz,1H), 3.90 (s, 2H), 3.63 (q, J=6.1, 5.3 Hz, 4H), 2.80-2.66 (m, 2H), 2.26(d, J=10.4 Hz, 1H), 1.90 (dd, J=11.9, 5.6 Hz, 1H), 1.68 (q, J=5.1, 4.7Hz, 2H), 1.61 (d, J=5.3 Hz, 10H), 1.47 (t, J=12.2 Hz, 1H), 1.04 (s, 9H),0.88 (d, J=6.3 Hz, 3H).

The following compound can be synthesized using the procedures describedherein:

6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[[2-(1-piperidyl)-3-pyridyl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2670)

PREPARATION 144:N-[(6-amino-2-pyridyl)sulfonyl]-3-(3-fluoro-5-isobutoxy-phenyl)-5-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrazine-2-carboxamide(Compound 2673) Step 1:3,5-dichloro-N-[(6-nitro-2-pyridyl)sulfonyl]pyrazine-2-carboxamide

To a stirred heterogeneous mixture of 3,5-dichloropyrazine-2-carboxylicacid (2.21 g, 11.5 mmol) in anhydrous CH₂Cl₂ (20 mL), thionyl chloride(7.5 mL, 103 mmol) was added under an atmosphere of nitrogen, followedby anhydrous DMF (30 mg, 0.41 mmol) and the reaction mixture was stirredat room temperature for 1 hour. The reaction mixture was evaporated,dissolved in CH₂Cl₂ (40 mL) and added dropwise to a solution of6-nitropyridine-2-sulfonamide (2.32 g, 11.5 mmol) with triethylamine(8.5 mL, 61.0 mmol) at 0° C., stirred overnight (24 h) while allowing towarm to ambient temperature. The reaction mixture was concentrated underreduced pressure. The residue was partitioned between CH₂Cl₂ (10 mL) andice-water (200 mL) and acidified with 2 M HCl to pH about 4.0. Theresulting solid was filtered, the layers separated and the aqueous layerwas extract with CH₂Cl₂ (3×50 mL). The combined organics were washedsequentially with 1N HCl, saturated sodium chloride solution then driedover sodium sulfate, filtered and evaporated under reduced pressure. Thecrude material was purified by triturating with dichloromethane (10 mL),filtration and drying to give3,5-dichloro-N-[(6-nitro-2-pyridyl)sulfonyl]pyrazine-2-carboxamide (2.90g, 67%) as a white solid. ESI-MS mtz calc. 376.93884, found 378.0(M+1)⁺; Retention time: 0.6 minutes.

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-3,5-dichloro-pyrazine-2-carboxamide

To a solution of3,5-dichloro-N-[(6-nitro-2-pyridyl)sulfonyl]pyrazine-2-carboxamide (830mg, 2.20 mmol) in THF (8 mL) and EtOH (4 mL), iron (Fe) powder (613 mg,11.0 mmol) was added, followed by HCl (6 N) (1.8 mL of 6.0 M, 10.80mmol). The reaction mixture was heated at 60° C. for 15 min. Aftercooling to room temperature, the reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with EtOAc (50 mL) and washed with NaOH (4 mL, 1 N). The layerswere filtered again and the aqueous layer was acidified to pH 2 with theaddition of 1 N HCl (aq) and extracted with EtOAc (2×50 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude material was purified from by silica gelcolumn chromatography using 0-20% MeOH in CH₂Cl₂ as eluent to giveN-[(6-amino-2-pyridyl)sulfonyl]-3,5-dichloro-pyrazine-2-carboxamide (404mg, 53%) ESI-MS m/z calc. 346.96466, found 348.0 (M+1)⁺; Retention time:0.53 minutes.

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-3-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrazine-2-carboxamideand(S)—N-((6-aminopyridin-2-yl)sulfonyl)-3-chloro-5-(2,2,4-trimethylpyrrolidin-1-yl)pyrazine-2-carboxamide

To a solution ofN-[(6-amino-2-pyridyl)sulfonyl]-3,5-dichloro-pyrazine-2-carboxamide (36mg, 0.10 mmol) in DMSO (142 μL), DTF,A (90 μL, 0.52 mmol) and(4S)-2,2,4-trimethylpyrrolidine (32 mg, 0.26 mmol) was added. Thereaction mixture was stirred for 6 hours at 85° C. The cooled reactionwas purified via reverse phase HPLC-MS method using a dual gradient runfrom 15-99% mobile phase B over 15.0 minutes (mobile phase A=H₂O (5 mMHCl), mobile phase B=acetonitrile) to yield a mixture ofN-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-3-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrazine-2-carboxamideand(S)—N-((6-aminopyridin-2-yl)sulfonyl)-3-chloro-5-(2,2,4-trimethylpyrrolidin-1-yl)pyrazine-2-carboxamide(28 mg, 64%) ESI-MS m/z calc. 424.10843, found 425.2 (M+1)⁺.

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-3-(3-fluoro-5-isobutoxy-phenyl)-5-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrazine-2-carboxamide(Compound 2673)

To a solution ofN-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-3-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrazine-2-carboxamide(S)—N-((6-aminopyridin-2-yl)sulfonyl)-3-chloro-5-(2,2,4-trimethylpyrrolidin-1-yl)pyrazine-2-carboxamide(60 mg, 0.14 mmol) and (3-fluoro-5-isobutoxy-phenyl)boronic acid (60 mg,0.28 mmol) in dioxane (3.0 mL) were added H₂O (1.0 mL), K₂CO₃ (78 mg,0.56 mmol) and bis(2-diphenylphosphanylcyclopenta-2,4-dien-1-yl)iron;dichloropalladium [Cl₂Pd(dppf).CH₂Cl₂] (8 mg, 0.011 mmol). Nitrogen wasbubbled for 5 min and the reaction mixture was sealed and stirred at120° C. under microwave radiation for 30 min. The reaction mixture wasallowed to cool to ambient temperature, filtered through a and purifiedvia reverse phase HPLC-MS (using a Luna C18 (2) column (75×30 mm, 5 μmparticle size) and a dual gradient run from 30-99% mobile phase B over30.0 minutes; mobile phase A=H₂O (5 mM HCl), mobile phase B=CH₃CN) tofurnishN-[(6-amino-2-pyridyl)sulfonyl]-3-(3-fluoro-5-isobutoxy-phenyl)-5-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyrazine-2-carboxamide(Compound 2673) (5.7 mg, 6%) as off-white solid. 1H NMR (400 MHz,DMSO-d6) δ 11.58 (s, 1H), 7.89 (s, 1H), 7.62-7.53 (m, 1H), 7.11 (d,J=7.3 Hz, 1H), 6.88-6.79 (m, 2H), 6.75-6.69 (m, 1H), 6.66 (d, J=8.3 Hz,1H), 6.52 (s, 2H), 3.83 (t, J=9.1 Hz, 1H), 3.74 (d, J=6.5 Hz, 2H), 3.12(t, J=10.4 Hz, 1H), 2.47-2.35 (m, 1H), 2.02 (dd, J=12.8, 6.3 Hz, 2H),1.61 (d, J=12.2 Hz, 1H), 1.56 (s, 3H), 1.45 (s, 3H), 1.10 (d, J=6.4 Hz,3H), 0.96 (d, J=6.8 Hz, 6H). ESI-MS m/z calc. 556.2268, found 557.4(M+1)⁺; Retention time: 2.15 minutes.

PREPARATION 145:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2679) Step 1:4-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid

To 6-bromo-4-chloro-pyridine-3-carboxylic acid (205 mg, 0.865 mmol),(3-fluoro-5-isobutoxy-phenyl)boronic acid (184 mg, 0.865 mmol), andpalladium;triphenylphosphane (30.0 mg, 0.0260 mmol) in dioxane (4 mL)was added solution of potassium carbonate (1.73 mL of 2 M, 3.46 mmol)under an atmosphere of nitrogen and the reaction mixture was stirred at80° C. for 10 h. The reaction mixture was concentrated under reducedpressure, partitioned between water (15 mL) and EtOAc (15 mL). Theaqueous layer was acidified with HCl and washed with EtOAc (3×15 mL).The combined organic layers was washed with brine (1×25 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Thesolid obtained was washed with hexanes to give4-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (232mg, 83%) as a tan solid. ESI-MS m/z calc. 323.07245, found 324.1 (M+1)⁺;Retention time: 0.74 minutes.

Step 2:4-chloro-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-nitro-2-pyridyl)sulfonyl]pyridine-3-carboxamide

4-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (104mg, 0.32 mmol) and SOCl₂ (190 mg, 116 μL, 1.60 mmol) with a drop of DMFwas stirred at ambient temperature for 30 minutes. The volatiles wereremoved under reduced pressure. In another flask,6-nitropyridine-2-sulfonamide (65 mg, 0.32 mmol) and TEA (97 mg, 134 4,0.96 mmol) in DCM (1.2 mL) was cooled in an ice-water bath. A solutionof the acid chloride generated in DCM was added slowly. The reactionmixture was stirred in ice-water bath and allowed to reach roomtemperature. The reaction mixture was diluted with DCM, washed with 1NHCl, saturated NaHCO3, and brine. The organics were separated and driedover sodium sulfate and evaporated under reduced pressure to give4-chloro-6-(3-fluoro-5-isobutoxy-phenye-N-[(6-nitro-2-pyridyl)sulfonyl]pyridine-3-carboxamide(157 mg, 97%) ESI-MS m/z caic. 508.06195, found 509.1 (M+1)⁺; Retentiontime: 0.74 minutes.

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-4-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide

4-chloro-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-nitro-2-pyridyl)sulfonyl[pyridine-3-carboxamide(123 mg, 0.242 mmol) was dissolved in THF (615 μL) and EtOH (615 μL).Powdered Fe (135 mg, 2.42 mmol) with HCl (80.6 μL of 6 M, 0.483 mmol)was added. The reaction mixture was heated at 65° C. for 10 min. Aftercooling to room temperature, the reaction mixture was filtered, thefiltrate was diluted with EtOAc and washed with NaOH (4 mL, 1 N). Thelayers were filtered again and aqueous layer was acidified to pH 2 withthe addition of aqueous HCl and extracted with EtOAc (1×8 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure to giveN-[(6-amino-2-pyridyl)sulfonyl[-4-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(61 mg, 53%) as a yellow powder. ESI-MS m/z calc. 478.08777, found 479.1(M+1)⁺; Retention time: 0.69 minutes.

Step 4:N-[(6-amino-2-pyridyl)sulfonyl[-6-(3-fluoro-5-isobutoxy-phenyl)-4-[(4S)-2,2,4-trimethylpyrrolidin-1-yl[pyridine-3-carboxamide(Compound 2679)

To a solution ofN-[(6-amino-2-pyridyl)sulfonyl]-4-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(24 mg, 0.050 mmol) in DMSO (0.1 mL) was added CsF (23 mg, 0.15 mmol)and (4S)-2,2,4-trimethylpyrrolidine (27 mg, 0.15 mmol). The reactionmixture was sealed and stirred at 120° C. overnight. The reactionmixture was cooled, diluted with DMSO and purified via HPLC/MS utilizinga gradient of 1-99% acetonitrile in 5 mM aq HCl to yieldN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2679) (5 mg, 19%). ESI-MS m/z calc. 555.23157, found 556.4(M+1)⁺; Retention time: 1.47 minutes.

PREPARATION 146:N-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxyethoxy)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2678)

N-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 852) (25 mg, 0.059 mmol), 2-ethoxyethanol (53 mg, 57 μL, 0.59mmol), NaH (7.0 mg, 0.29 mmol), and scandium(3+)trifluoromethanesulfonate (2.9 mg, 0.0058 mmol) were dissolved in DMSO(0.5 mL) and heated at 120° C. for 8 h. The reaction mixture waspartitioned between ethyl acetate and a 1N aq HCl solution. The organicswere separated, washed with brine, dried over sodium sulfate andevaporated under reduced pressure. The crude material was purified bysilica gel chromatography eluting with 0-100% ethyl acetate in hexanesto giveN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxyethoxy)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2678) (7 mg, 25%) ESI-MS m/z calc. 477.2046, found 478.4(M+1)⁺; Retention time: 1.25 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(2-amino-3-pyridyl)sulfonyl]-6-methoxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2704),-   N-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxyethoxy)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2705) and-   N-[(2-amino-3-pyridyl)sulfonyl]-642-(2-ethoxyethoxy)ethoxy]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2706).

PREPARATION 147:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-iodo-2,6-dimethyl-phenoxy)pyridine-3-carboxamide(Compound 2671)

ToN-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(69 mg, 0.14 mmol) and 4-iodo-2,6-dimethyl-phenol (71 mg, 0.29 mmol) inNMP (4 mL) was added NaH (17 mg, 0.43 mmol). The reaction mixture wasstirred for 5 min at rt then stirred at 150° C. for 2 h. The reactionmixture was quenched with NH₄Cl soln, the crude mixture purified byreverse phase silica gel column chromatography using 10-100% ACN inWater (TFA modifier) as eluent to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-iodo-2,6-dimethyl-phenoxy)pyridine-3-carboxamide(Compound 2671) (8 mg, 7%). 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J=8.1 Hz,1H), 7.76-7.68 (m, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H),7.47 (s, 2H), 7.04-6.95 (m, 3H), 6.76 (d, J=8.2 Hz, 1H), 6.63 (dt,J=10.3, 2.2 Hz, 1H), 3.56 (t, J=7.0 Hz, 2H), 2.13-2.06 (m, 6H), 1.01 (t,J=6.6 Hz, 6H), 0.85 (t, J=6.7 Hz, 3H), 0.47 (s, 1H). ESI-MS m/z found691.4 (M+1)⁺; Retention time: 0.83 minutes

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-benzoyl-2,6-dimethyl-phenoxy)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide    (Compound 2715) and-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(4-benzoyl-2,6-dimethyl-phenoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 2669).

PREPARATION 148:N-[(6-amino-2-pyridyl)sulfonyl]-2,6-bis(4-benzoyl-2,6-dimethyl-phenoxy)pyridine-3-carboxamide(Compound 970)

To N-[(6-amino-2-pyridyl)sulfonyl]-2,6-dichloro-pyridine-3-carboxamide(487 mg, 1.40 mmol) in DMF (4 mL) was added(4-hydroxy-3,5-dimethyl-phenyl)-phenyl-methanone (390 mg, 1.57 mmol) andNaH (140.3 mg, 3.508 mmol). The reaction mixture was stirred at rt for20 min, then 150° C. for 1 hr. The crude mixture purified by reversephase silica gel column chromatography using 0-80% ACN in Water (TFAmodifier) as eluent, then further purified by silica gel columnchromatography eluting with 30-100% EtOAc in heptane to giveN-[(6-amino-2-pyridyl)sulfonyl]-2,6-bis(4-benzoyl-2,6-dimethyl-phenoxy)pyridine-3-carboxamide(Compound 970) (51 mg, 4%). 1H NMR (300 MHz, DMSO) δ 8.24 (dd, J=15.6,8.2 Hz, 1H), 7.80-7.66 (m, 1H), 7.66-7.39 (m, 10H), 7.31-7.22 (m, 4H),7.11 (d, J=7.2 Hz, 1H), 6.74 (t, J=10.3 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H),6.27 (s, 2H), 1.92 (d, J=1.9 Hz, 12H); ESI-MS m/z found 727.5 (M+1)⁺;Retention time: 0.68 minutes (4 min run).

PREPARATION 149:N-[(6-fluoro-2-pyridyl)sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 698) Step 1: Methyl6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate

A mixture of methyl 2-chloro-6-phenyl-pyridine-3-carboxylate (224 mg,0.904 mmol), 2,4,6-trimethylphenol (123 mg, 0.904 mmol), cesiumcarbonate (295 mg, 0.904 mmol) and DMF (3.14 mL) was heated at 80° C.overnight. The reaction mixture was cooled to room temperature beforepartitioned between ethyl acetate and 1N HCl. The layers were separatedand the aqueous layer was extracted with ethyl acetate (2×). Thecombined organics were washed with brine, dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to column chromatography (0-25% ethyl acetate/hexanes) to givemethyl 6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (250mg, 71%). ESI-MS m/z calc. 347.15213, found 348.4 (M+1)⁺; Retentiontime: 2.28 minutes (3 min run).

Step 2: 6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid

[Methyl 6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylate (562mg, 1.62 mmol) was dissolved in methanol (8 mL): THF (3 mL) and NaOH(8.09 mL of 1 M, 8.09 mmol) was added. The reaction mixture was heatedat 65° C. for 3 h. The reaction mixture was poured over ice andacidified with 6M HCl. The resulting white solid was collected and thendissolved in methanol and evaporated under reduced pressure to give6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (466 mg,86%) ESI-MS m/z calc. 333.1365, found 334.2 (M+1)⁺; Retention time: 0.74minutes.

Step 3:N-[(6-fluoro-2-pyridyl)sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 698)

To 6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid (150mg, 0.450 mmol), HATU (171 mg, 0.450 mmol), DMF (1.5 mL), andtriethylamine (137 mg, 188 μL, 1.35 mmol) was added6-fluoropyridine-2-sulfonamide (79.3 mg, 0.450 mmol) was added and thereaction mixture was allowed to stir at 65° C. for 1 h. The reactionmixture was filtered and purified via HPLC (1%-99%) ACN:H₂O with a 0.1%HCl modifier to giveN-[(6-fluoro-2-pyridyl)sulfonyl]-6-phenyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide(Compound 698) (79 mg, 36%) 1H NMR (400 MHz, DMSO-d6) δ 8.37 (q, J=7.8Hz, 1H), 8.16 (dd, J=7.5, 2.1 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.80-7.73(m, 3H), 7.59 (dd, J=8.3, 2.2 Hz, 1H), 7.41 (ddt, J=5.5, 3.8, 2.2 Hz,3H), 6.94 (s, 2H), 2.28 (s, 3H), 2.01 (s, 6H). ESI-MS m/z calc.491.1315, found 492.4 (M+1)⁺; Retention time: 2.19 minutes.

PREPARATION 150: (S)-2,2-dimethyl-4-(methyl-d₃)pyrrolidine-3,3-d₂ Step1: Methyl-d₃ 4-methyl-2-(methyl-d₃)-4-nitropentanoate-3,3-d₂

A 500-mL, three-neck round bottom flask equipped with a magnetic stirbar, a nitrogen line and a J-Kem thermocouple with heating mantle wascharged with 2-nitropropane (34.3 g, 385 mmol) and d₈-methylmethacrylate (50 g, 462 mmol) was stirred at ambient temperature when1,8-diazabicyclo[5.4.0]undec-7-ene (1.47 g, 9.63 mmol) was added in oneportion. The reaction solution exothermed from 20 to 40° C. and wasallowed to stir without heating or cooling for 16 h. The reactionmixture was heated at 80° C. for 4 h. The reaction mixture was dilutedwith MTBE (170 mL), washed with 1 M HCl (15 mL), dried (MgSO₄), filteredand concentrated under reduced pressure to afford methyl-d₃4-methyl-2-(methyl-d₃)-4-nitropentanoate-3,3-d₂ as light yellow oil (75g, 99%), which was used in the next step without further purification.

Step 2: Methyl-d₃ (S)-4-methyl-2-(methyl-d₃)-4-nitropentanoate-3,3-d₂

A 5-L, three-neck round bottom flask equipped an overhead mechanicalstirrer, a nitrogen line and a J-Kem thermocouple with heating mantlewas charged with methyl-d₃4-methyl-2-(methyl-d₃)-4-nitropentanoate-3,3-d₂ (75 g, 380 mmol) and pH7.5 Na-phosphate buffer @ 0.8 M (2000 mL). To this was added lipase fromRhizomucor miehei (sigma L4277, palatase from Novozymes) (37.5 mL) andstirred at 30° C. for 25 h. The reaction mixture was extracted twicewith MTBE (1 L each time). The combined organics were washed with NaHCO₃(5 vol) twice, brine (5 vol), dried over sodium sulfate and concentratedin vacuo to afford methyl-d₃(S)-4-methyl-2-(methyl-d₃)-4-nitropentanoate-3,3-d₂ as pale yellow oil(32.5 g, 43% yield).

Step 3: (S)-5,5-dimethyl-3-(methyl-d₃)pyrrolidin-2-one-4,4-d₂

A high-pressure vessel (Parr shaker bottle, 500 mL) was purged with andmaintained under N₂. The vessel was charged sequentially with DIwater-rinsed (3×) damp Raney®2800 Ni (6.1 g), methyl-d3(S)-4-methyl-2-(methyl-d3)-4-nitropentanoate-3,3-d2 (32.5 g, 165 mmol)and EtOH (290 mL). The vessel was sealed and evacuated/backfilled withN₂ (3×). With no stirring, the vessel was then evacuated and backfilledwith H₂ (30 psi). The Parr bottle was shaken while heating the reactionmixture at 60° C., and the H₂ pressure was maintained at 30 psi for 8hours. The vessel was evacuated/backfilled with N₂ (3 ×) and thecatalyst/Celite were removed by vacuum filtration (Celite pad; N₂blanket). The flask/filter-pad was washed with EtOH (3×50 mL). Thefiltrate and washes were combined and concentrated in vacuo to afford(S)-5,5-dimethyl-3-(methyl-d₃)pyrrolidin-2-one-4,4-d₂ (20 g, 92%) aswhite solid.

Step 4: (S)-2,2-dimethyl-4-(methyl-d₃)pyrrolidine-3,3-d₂

A 1-L, three-neck round bottom flask equipped an overhead mechanicalstirrer, a nitrogen line and a J-Kem thermocouple was charged with LAHpellets (7.6 g, 202 mmol) in THF (80 mL). A solution of(S)-5,5-dimethyl-3-(methyl-d₃)pyrrolidin-2-one-4,4-d₂ (20 g, 151 mmol)in THF (120 mL) was added to the suspension over 30 minutes whileallowing the reaction temperature to rise to 60° C. The reactiontemperature was increased to near reflux (−68° C.) and maintained for 16h. The reaction mixture was cooled to below 40° C. and diluted with MTBE(200 mL). The reaction mixture was quenched carefully with drop-wiseaddition of a saturated aqueous solution of Na₂SO₄ (1 vol) over 2 h.After the addition was completed, the reaction mixture was cooled to RT.The solid was removed by filtration (Celite pad) and washed with EtOAc(4 vol). With external cooling and N₂ blanket, the filtrate and washingswere combined and treated with drop-wise addition of anhydrous 4 M HClin dioxane (1 equiv.) while maintaining the temperature below 20° C.After the addition was completed (20 min), the resultant suspension wasconcentrated under reduced pressure at 45° C. The suspension wasbackfilled with heptanes (4 vol) twice during concentration. Thesuspension was cooled to below 30° C. when the solid was collected byfiltration under a N₂ blanket. The solid was dried under high vacuum at45° C. to afford (S)-2,2-dimethyl-4-(methyl-d₃)pyrrolidine-3,3-d2 (17.5g, 75%) as a white, crystalline solid.

PREPARATION 151: (6-((propan-2-yl-d7)oxy)pyridin-3-yl)boronic acid Step1: 5-bromo-2-((propan-2-yl-d7)oxy)pyridine

To NaH (245 g, 10.2 mmol) slurried in DMF (7 mL) was added d7-IPA (610mg, 9.09 mmol) and the reaction mixture was stirred for 30 min at roomtemperature. 5-bromo-2-fluoropyridine (1.00 g, 5.68 mmol) was added andthe reaction mixture was heated to 120° C. for 2.5 h, then an additionalaliquot of NaH (40 mg) and d7-IPA (0.07 mL) was added. After a further 2h of heating, the reaction mixture was allowed to cool to roomtemperature. Water (21 mL), followed by MTBE (14 mL) was added, andafter stirring, the layers were separated. The organic layer was washedwith water (14 mL), dried over sodium sulfate, filtered and concentratedto give 5-bromo-2-((propan-2-yl-d7)oxy)pyridine. 1H NMR (400 mHz) δ 8.17(m, 1H), 7.60 (dd, J=8.8, 2.6 Hz, 1H), 6.58 (dd, J=8.8, 0.7 Hz, 1H).

Step 2: (6-((propan-2-yl-d7)oxy)pyridin-3-yl)boronic acid

A mixture of5-bromo-2-[1,2,2,2-tetradeuterio-1-(trideuteriomethyl)ethoxy]pyridine(1.24g, 5.00 mmol), bis(pinacolato)diboron (1.52 g, 6.00 mmol), KOAc(1.47 g, 15.0 mmol), Pd(OAc)₂ (44.9 mg, 0.20 mmol), X-Phos (119 mg, 0.25mmol) in 2-MeTHF (11 mL) was heated to 80° C. for 2.5 h under anatmosphere of nitrogen. The reaction mixture was allowed to cool, thenwater (8 mL) was added and the reaction mixture was filtered throughCelite pad washing with 2-MeTHF (2×5 mL). The layers were separated andthe organic layer dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude material was dissolved in 2-MeTHF (12mL), 10% aq w/v NaOH was added and the reaction mixture was stirred. Thelayers were separated, the aqueous layer was acidified to pH 5 with concHCl and stirred with 2-MeTHF (12 mL), then separated, the organic layerdried over sodium sulfate, filtered and concentrated under reducedpressure to give (6-((propan-2-yl-d7)oxy)pyridin-3-yl)boronic acid.

PREPARATION 152:N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2708) Step 1:1-bromo-3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]benzene

To 3-bromo-5-fluoro-phenol (6.00 g, 31.41 mmol) in DMF (60 mL) wasslowly added NaH (1.38 g, 34.55 mmol) and the reaction mixture wasstirred at ambient temperature for 15 min. To the mixture was added NaI(1.18 g, 7.85 mmol), followed2-(bromomethyl)-1,1,1,2,3,3,3-heptadeuterio-propane (5.05 g, 34.55mmol). The reaction mixture was stirred at 80° C. for 6 h. The reactionmixture was cooled to ambient temperature and slowly quenched with water(120 mL). The reaction mixture was extracted with EtOAc (240 mL) and theorganic phase separated. The organic phase was washed with brine, driedover MgSO₄, filtered and concentrated in vacuo. The crude light yellowoil was purified by silica gel column chromatography eluting with 0-100%EtOAc/hexanes to give1-bromo-3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyppropoxy]benzene(6.8 g, 85%). 1H NMR (400 MHz, Chloroform-d) δ 6.90-6.77 (m, 2H), 6.55(dt, J=10.7, 2.2 Hz, 1H), 3.75-3.61 (m, 2H).

Step 2:2-[3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To the1-bromo-3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]benzene(10.8 g, 42.50 mmol) in dioxane (162 mL) was addedbis(dipinacolato)diboron (16.2 g, 63.75 mmol) and KOAc (12.5 g, 127.5mmol) and the reaction mixture was purged with N₂ for 20 min. To thereaction mixture was added PdCl₂(dppf)₂.CH₂Cl (1.74 g, 2.13 mmol) andthe reaction mixture was heated to 100° C. for 3 h. The reaction mixturewas cooled to ambient temperature and filtered through celite andconcentrated in vacuo affording a dark oil. The material was purifiedusing silica gel column chromatography eluting with 0-100% EtOAc/hexanesto give2-[3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(8.92 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ 6.99 (dd, J=2.4, 0.8 Hz, 1H),6.96-6.87 (m, 2H), 3.76 (s, 2H), 1.29 (s, 12H).

Step 3:N-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2708)

ToN-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 852) (1.4 g, 3.3 mmol) in 1-propanol (14 mL) and water (4.2mL) was slowly added K₂CO₃ (1.4 g, 9.9 mmol), followed by1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ide;3-chloropyridine;palladium(2+);dichloride(45 mg, 0.06 mmol) and the reaction mixture was heated to 80° C. To thereaction mixture was slowly added2-[3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.2 g, 4.1 mmol) in 1-propanol (2.8 mL). The reaction mixture wasstirred at 80° C. for 19 h. The reaction mixture was cooled to ambienttemperature and slowly added to water (80 mL) containing HCl (20 mL of 1M, 19.8 mmol). The reaction mixture was diluted with EtOAc (100 mL) andthe organic phase separated. The organic phase was washed with brine,dried over MgSO4, filtered over celite and concentrated in vacuo. Thecrude product was purified by silica gel column chromatography elutingwith 0-10% MeOH/DCM, then by reverse phase column chromatography elutingwith 5-100% ACN/Water to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 2708) (495 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s,1H), 7.78 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.4, 7.3 Hz, 1H), 7.53-7.45 (m,1H), 7.40 (dt, J=10.0, 2.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.20 (d,J=7.3 Hz, 1H), 6.89 (dt, J=10.7, 2.3 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H),6.49 (s, 2H), 3.83 (s, 2H), 2.76-2.54 (m, 3H), 2.22 (s, 1H), 1.88 (dd,J=11.9, 5.7 Hz, 1H), 1.60 (d, J=5.7 Hz, 6H), 1.42 (t, J=12.1 Hz, 1H),0.88 (d, J=6.2 Hz, 3H). ESI-MS m/z calc. 562.2755, found 563.36 (M+1)+;Retention time: 2.73 minutes.

The following compound can be synthesized using the procedures describedherein:

-   N-(benzenesulfonyl)-6-[3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyppropoxy]phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 2713).

PREPARATION 153:5-tert-butyl-N-(2-cyanophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 266) Step 1: Ethyl3-(tert-butyl)-1-(2,4,6-trimethylbenzyl)-1H-pyrazole-5-carboxylate

A mixture of ethyl 5-tert-butyl-4H-pyrazole-3-carboxylate (0.5 g, 2.5mmol), 2-(bromomethyl)-1,3,5-trimethyl-benzene (0.5 g, 2.5 mmol), andK₂CO₃ (0.7 g, 5.1 mmol) in DMF (5 mL) was heated to 80° C. overnight. Afurther aliquot of 2-(bromomethyl)-1,3,5-trimethyl-benzene (200 mg) andK₂CO₃ (0.7 g, 5.1 mmol) were added and the temperature was increased to85° C. The reaction mixture was heated overnight. The reaction mixturewas cooled, water (20 ml) was added and extracted with ethyl acetate(2×50 ml). The organic layers were dried over Na₂SO₄, concentrated invacuo, and purified by silica gel column chromatography.

Step 2:5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylic acid

A solution of ethyl5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylate(2.0 g, 6.0 mmol) and sodium hydroxide (1.9 g, 48 mmol) in THF (10 mL)and water (10 mL) was stirred at 60° C. for 17 hours. The reactionmixture was cooled to room temperature and acidified with 1 Mhydrochloric acid. The white precipitate was filtered, washed withwater, and dried under vacuum to give5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylic acid(1.7 g, 96%) as a white powder. 1H NMR (400 MHz, DMSO) δ 6.92-6.77 (m,2H), 6.67 (s, 1H), 5.63 (s, 2H), 2.25 (dd, J=23.8, 13.5 Hz, 9H), 1.13(d, J=10.4 Hz, 9H). ESI-MS m/z calc. 300.18378, found 301.0 (M+1)⁺;Retention time: 2.06 minutes.

Step 3:5-tert-butyl-N-(2-cyanophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 266)

5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxylic acid(30mg, 0.1 mmol), 2-cyanobenzenesulfonamide (18 mg, 0.1 mmol), HATU (38mg, 0.1 mmol) and DIEA (39 mg, 52 μL, 0.3 mmol) were combined in DMF(1.5 mL) and heated at 60° C. for 16 h. The reaction mixture wasfiltered and purified by HPLC/MS utilizing a gradient of 1-99%acetonitrile in 5 mM aq HCl to yield5-tert-butyl-N-(2-cyanophenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide(Compound 266) (11 mg, 24%) 1H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J=7.9,1.3 Hz, 1H), 8.12 (dd, J=7.6, 1.4 Hz, 1H), 7.97 (td, J=7.8, 1.5 Hz, 1H),7.90 (td, J=7.6, 1.3 Hz, 1H), 7.00 (s, 1H), 6.74 (s, 2H), 5.43 (s, 2H),2.17 (s, 3H), 2.06 (s, 6H), 1.16 (s, 9H). ESI-MS m/z calc. 464.1882,found 465.4 (M+1)⁺; Retention time: 2.29 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-(benzenesulfonyl)-5-tert-butyl-2-[1-(2,4,6-trimethylphenyl)ethyl]pyrazole-3-carboxamide    (Compound 201),-   N-(benzenesulfonyl)-5-tert-butyl-2-[[2-fluoro-5-(trifluoromethyl)phenyl]methyl]pyrazole-3-carboxamide    (Compound 35),-   5-tert-butyl-N-((3-(dimethylamino)phenylisulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 270),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trichlorophenyl)methyl]pyrazole-3-carboxamide    (Compound 303),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(4-tert-butyl-2,6-dimethyl-phenyl)methyl]pyrazole-3-carboxamide    (Compound 156),-   N-(benzenesulfonyl)-5-[4-(difluoromethypphenyl]-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 119),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[[2-chloro-6-(trifluoromethyl)phenyl]methyl]pyrazole-3-carboxamide    (Compound 189),-   5-tert-butyl-N-((3-(dimethylamino)-2-methyl-phenyl]sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 104),-   N-(3-amino-2-methyl-phenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 123),-   5-tert-butyl-N-(1-methylindol-7-yl)sulfonyl-2-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]pyrazole-3-carboxamide    (Compound 276),-   5-tert-butyl-N-(m-tolylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 80),-   5-tert-butyl-N-(5-quinolylsulfonyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 352),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,3,5,6-tetramethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 317),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(2-thienylsulfonyepyrazole-3-carboxamide    (Compound 77),-   N-(benzenesulfonyl)-5-tert-butyl-2-[(2,4,6-trichlorophenyl)methyl]pyrazole-3-carboxamide    (Compound 145),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(2-methoxy-3-methyl-phenyl)sulfonyl-pyrazole-3-carboxamide    (Compound 59),-   N-(benzenesulfonyl)-5-tert-butyl-2-(1-naphthylmethyl)pyrazole-3-carboxamide    (Compound 328),-   5-tert-butyl-N-[3-(methylamino)phenyl]sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 249),-   5-tert-butyl-N-[1-(2-hydroxyethyl)indol-4-yl]sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 188),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-4-methyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 20),-   5-tert-butyl-N-(3-hydroxyphenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 84),-   5-tert-butyl-N-(1-methylimidazol-4-yl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 1568),-   N-(benzenesulfonyl)-5-tert-butyl-2-[(3-pyrrol-1-ylphenyl)methyl]pyrazole-3-carboxamide    (Compound 108),-   5-tert-butyl-N-(1H-indol-4-ylsulfonyl)-2-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]pyrazole-3-carboxamide    (Compound 60),-   N-(3-acetylphenyl)sulfonyl-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 332),-   N-(benzenesulfonyl)-5-tert-butyl-2-[[5-methyl-2-(trifluoromethyl)phenyl]methyl]pyrazole-3-carboxamide    (Compound 304),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]pyrazole-3-carboxamide    (Compound 239),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[1-(o-tolypethyl]pyrazole-3-carboxamide    (Compound 342),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-tert-butyl-4-methyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 356),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-(1-cyclohexylethyl)pyrazole-3-carboxamide    (Compound 287),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-(1-phenylpropyl)pyrazole-3-carboxamide    (Compound 165),-   5-tert-butyl-N-(4-hydroxyphenyl)sulfonyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 269),-   N-(3-aminophenyl)sulfonyl-5-(1-methylcyclopropyl)-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 158),-   N-(benzenesulfonyl)-5-tert-butyl-2-[[2-methyl-3-(trifluoromethyl)phenyl]methylipyrazole-3-carboxamide    (Compound 98),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 185),-   N-(3-aminophenyl)sulfonyl-5-isobutyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 167),-   N-[(6-amino-2-pyridyl)sulfonyl]-5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 173),-   N-(benzenesulfonyl)-5-tert-butyl-2-[2-(2-methoxyphenyeethyl]pyrazole-3-carboxamide    (Compound 157),-   5-tert-butyl-N-[(3-methoxy-2-pyridyl)sulfonyl]-2-[(2,4,6-trimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 44),-   N-(3-aminophenyl)sulfonyl-5-tert-butyl-2-(1-naphthylmethyl)pyrazole-3-carboxamide    (Compound 295),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(2-fluorophenyl)sulfonyl-pyrazole-3-carboxamide    (Compound 57),-   N-(4-aminophenyl)sulfonyl-5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 81),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(1H-indazol-4-ylsulfonyl)pyrazole-3-carboxamide    (Compound 86),-   N-(3-amino-4-fluoro-phenyl)sulfonyl-5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 150),-   5-tert-butyl-N-(2,6-difluorophenyl)sulfonyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 170),-   5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]-N-(1-methylindol-4-yl)sulfonyl-pyrazole-3-carboxamide    (Compound 210),-   5-tert-butyl-N-(2,3-dihydrobenzofuran-7-ylsulfonyl)-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 211),-   N-(benzenesulfonyl)-5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 257),-   N-(3-amino-4-methyl-phenyl)sulfonyl-5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxamide    (Compound 312) and-   N-(3-aminophenyl)sulfonyl-1-[(2,4,6-trimethylphenyl)methyl]benzimidazole-2-carboxamide    (Compound 71).

PREPARATION 154: (3S)-3,5,5-trimethylpyrrolidin-2-one Step 1:Methyl-2,4-dimethyl-4-nitro-pentanoate

THF (4.5 L) was added to a 20 L glass reactor and stirred under anatmosphere of nitrogen at room temperature. 2-Nitropropane (1.5 kg) andDBU (1.282 kg, 0.5 equiv.) were then charged to the reactor (immediateyellow color observed) and the jacket temperature was increased to 50°C. Once the reactor contents were close to 50° C., methyl methacrylate(1.854 kg, 1.1 equiv.) was added slowly over 100 minutes. The reactiontemperature was maintained at or close to 50° C. with reactioncompletion reached at 21 h. During the course of the reaction, a colorchange from yellow to deep green was observed. The reaction mixture wasconcentrated in vacuo then transferred back to the reactor and dilutedwith MTBE (14 L). 2 M HCl (7.5 L) was added and this was stirred for 5minutes then allowed to settle. Two clear layers were visible—a loweryellow aqueous phase and an upper green organic phase. The aqueous wasremoved and the organic was stirred again with 2 M HCl (3 L). Afterseparation, the HCl washes were recombined and stirred with MTBE (3 L)for 5 minutes. The aqueous was removed and all of the organics werecombined in the reactor and stirred with water (3 L) for 5 minutes.After separation, the organics were concentrated in vacuo to afford acloudy green mobile film which was dried with MgSO₄ and filtered toafford racemic methyl-2,4-dimethyl-4-nitro-pentanoate (3.16 kg) as aclear green mobile oil (99% yield). ¹H NMR (400 MHz, Chloroform-d) δ3.68 (s, 3H), 2.56-2.35 (m, 2H), 2.11-2.00 (m, 1H), 1.56 (d, J=20.2 Hz,6H), 1.19 (d, J=6.8 Hz, 3H).

Step 2: Methyl (2S)-2,4-dimethyl-4-nitro-pentanoate

A reaction vessel was set up with methyl 2,4-dimethyl-4-nitro-pentanoate(7 kg, 105.7 mmol) and stirred with 70 L of pH 6.5 K phosphate buffer @0.1 M. To this was added 3.5 L lipase (palatase from Novozymes) andstirred at 34° C. for ˜43 h. The pH of the reaction was maintained at pH6.5 by pH Stat dosing K₂CO₃ (aq. Soln). The reaction mixture wasextracted with MTBE (2×5 vol, 1×2 vol). The combined MTBE layers werethen washed with 2 M Na₂CO₃ (4×2.5 vol), water (3 vol) and brine (3vol). The product was concentrated down to ˜10 L in the reactor bydistilling off the MTBE and transferred to a large rotary evaporator forfinal concentration to afford methyl(2S)-2,4-dimethyl-4-nitro-pentanoate as a mobile yellow oil (3072.2 g,44% yield).

Step 3: (3S)-3,5,5-trimethylpyrrolidin-2-one

A 20 L Hastelloy reactor vessel, purged with and maintained under N₂.The vessel was charged sequentially with DI water-rinsed, damp Raney® Ni(2800 grade, 250 g), methyl (2S)-2,4-dimethyl-4-nitro-pentanoate (1741g,9.2 mol) and ethanol (13.9 L, 8 vol). Stirring was commenced at 900 rpmand the reactor flushed with H₂ and maintained at ˜2.5 bar. After 5hours, the reaction mixture was filtered to remove Raney nickel andsolid cake rinsed with ethanol (3.5 L, 2 vol). The ethanolic solution ofproduct was concentrated in vacuo to reduce to a minimum volume ofethanol (˜1.5 volumes), then heptane (2.5 L) was added and thesuspension concentrated again to ˜1.5 volumes. This was repeated afurther 3 times, then the resulting suspension was cooled to 0-5° C. andfiltered under suction and washed with heptane (2.5 L). The product wasdried on the filter under vacuum for 20 minutes then transferred todrying trays and dried in a vacuum oven at 40° C. overnight (with N2bleed). This afforded (3S)-3,5,5-trimethylpyrrolidin-2-one as a whitecrystalline solid (2.042 kg, 87%). ¹H NMR (400 MHz, Chloroform-d) δ 6.39(s, 1H), 2.62 (ddq, J=9.9, 8.6, 7.1 Hz, 1H), 2.17 (ddd, J=12.4, 8.6, 0.8Hz, 1H), 1.56 (dd, J=12.5, 9.9 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.20(d, J=7.1 Hz, 3H).

PREPARATION 155:N-((2-aminopyridin-3-yl)sulfonyl)-6′-(((S)-1-hydroxypropan-2-yl)oxy)-6-((S)-2,2,4-trimethylpyrrolidin-1-yl)-[2,3′-bipyridine]-5-carboxamide(Compound 2690) Step 1:N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-fluoro-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

A mixture ofN-[(2-amino-3-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(3.8 g, 8.96 mmol), (6-fluoro-2-pyridyl)boronic acid (2.00 g, 14.2mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1.40 g, 2.32 mmol), and Na₂CO₃ (4.00 g,37.7 mmol) in dimethylformamide (80 mL) and water (20 mL) was degassedunder a stream of nitrogen and stirred at 100° C. for 18 hours.(6-Fluoro-2-pyridyl)boronic acid (0.90 g, 6.4 mmol),[1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.40 g, 0.55 mmol) were added, and the reaction mixturestirred at 100° C. for another day. The reaction mixture was filteredthrough a pad of Celite and the filtrate was diluted with water (300mL), adjusted to pH ˜7 and extracted with ethyl acetate (5×300 mL). Theextract was washed with brine (2×200 mL), dried over Na₂SO₄, andconcentrated. The residue purified by chromatography on silica gel,eluted with 0-100% ethyl acetate in hexanes, affording yellow foamproduct (2.2 g, 85% purity) and starting material (3) (560 mg).

Step 2:N-((2-aminopyridin-3-yl)sulfonyl)-6′-(((S)-1-(benzyloxy)propan-2-yl)oxy)-6-((S)-2,2,4-trimethyl-1-yl)-[2,3′-bipyridine]-5-carboxamide

Sodium hydride (44 mg, 1.1 mmol) (60 wt % in mineral oil) was added to asolution of (R)-1-benzyloxy-propan-2-ol (117 mg, 0.7 mmol) indimethylformamide (2.0 mL). After 5 minutes of stirring at roomtemperature,N-[(2-amino-3-pyridyl)sulfonyl]-6-(6-fluoro-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(108 mg, 0.18 mmol) was added. The reaction mixture was heated undermicrowave irradiation at 75° C. for 30 minutes. The reaction mixture wasquenched with water (10 mL), adjusted pH 3-4, and extracted with ethylacetate (2×10 mL). The combined extract was washed with brine (2×5 mL),dried over Na₂SO₄ and concentrated under reduced pressure to giveN-((2-aminopyridin-3-yl)sulfonyl)-6′-(((S)-1-(benzyloxy)propan-2-yl)oxy)-6-((S)-2,2,4-trimethyl-pyrrolidin-1-yl)-[2,3′-bipyridine[-5-carboxamide.ESI-MS m/z 631 (M+1)⁺.

Step 3:N-((2-aminopyridin-3-yl)sulfonyl)-6′-(((S)-1-hydroxypropan-2-yl)oxy)-6-((S)-2,2,4-trimethylpyrrolidin-1-yl)-[2,3′-bipyridine]-5-carboxamide(Compound 2690)

N-((2-aminopyridin-3-yl)sulfonyl)-6′-(((S)-1-(benzyloxy)propan-2-yl)oxy)-6-((S)-2,2,4-trimethyl-pyrrolidin-1-yl)-[2,3′-bipyridine[-5-carboxamidewas hydrogenated under 1 atmosphere of hydrogen with Pd/C (10%, 260 mg)in methanol (25 mL) at room temperature. After 4 hours, the catalyst wasremoved by filtration, evaporated under reduced pressure and purified bysilica gel column chromatography (0-10% of methanol in dichloromethane),followed by a further purification by silica gel column chromatographyeluted with 0-8% of methanol in a mixture solvent of ethyl acetate andhexanes in a ratio of 50/50 to giveN-((2-aminopyridin-3-yl)sulfonyl)-6′-(((S)-1-hydroxypropan-2-yl)oxy)-6-((S)-2,2,4-trimethylpyrrolidin-1-yl)-[2,3′-bipyridine]-5-carboxamide(Compound 2690) (9 mg). ESI-MS m/z 541 (M+1)⁺.

PREPARATION 156: Methyl2-(benzenesulfonyl)-3-[5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazol-3-yl]-3-oxo-propanoate(Compound 4) Step 1:5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carbonyl chloride

5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carboxylic acid(100 mg, 0.3492 mmol) was dissolved in thionyl chloride (41.54 mg, 25.47μL, 0.3492 mmol) and a drop of DMF was added. The reaction was stirredfor lh and evaporated to give the acid chloride, which was used withoutfurther purification.

Step 2: Methyl2-(benzenesulfonyl)-3-[5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazol-3-yl]-3-oxo-propanoate(Compound 4)

To 5-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazole-3-carbonylchloride

(40 mg, 0.13 mmol), methyl 2-(benzenesulfonyl)acetate (28 mg, 22 uL,0.13 mmol)and NaH (5 mg, 0.13 mmol) in DMF were stirred at roomtemperature for 15 minutes. The reactions were filtered and purified byreverse phase LC-MS (10-99% CH₃CN/H₂O, HCl modifier) to give methyl2-(benzenesulfonyl)-345-tert-butyl-2-[(2,6-dimethylphenyl)methyl]pyrazol-3-yl]-3-oxo-propanoate(Compound 4) (18 mg, 28%). ESI-MS m/z 483.4 (M+1)⁺; Retention time: 2.41minutes.

PREPARATION 157:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-(4-methoxyphenyl)vinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1535) Step 1:5-Iodo-6-tert-butyl-2-hydroxypyridine-3-carbonitrile

N-Iodosuccinimide (31.9 g, 142 mmol) was added to a solution of6-tert-butyl-2-hydroxypyridine-3-carbonitrile (10.0 g, 56.8 mmol) in amixture of 1,2-dichloroethane (120 mL) and trifluoroacetic acid (40 mL)and the reaction mixture was heated at 50° C. overnight. The solutionwas concentrated under reduced pressure and ethyl acetate (300 mL) wasadded. The organic layer was washed with 10% sodium thiosulfate solution(300 mL), water (2×200 mL) and brine (150 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography, eluting from 30% EtOAc inheptanes to 60% EtOAc in heptanes, to provide5-iodo-6-tert-butyl-2-hydroxypyridine-3-carbonitrile (15.85 g, 92%yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) ppm 1.57 (s, 9 H), 8.17(s, 1H). [M+H]⁺=303.0.

Step 2: 5-Iodo-6-tert-butyl-2-chloropyridine-3-carbonitrile

Phosphorus oxychloride (67.0 mL, 718 mmol) and phosphorus pentachloride(44.9 g, 216 mmol) were added to5-iodo-6-tert-butyl-2-hydroxypyridine-3-carbonitrile (21.7 g, 71.8 mmol)and the reaction mixture was refluxed overnight. The reaction mixturewas cooled to room temperature and concentrated under reduced pressureto remove most of the remaining phosphorus oxychloride. Water (caution:exotherm) followed by 50% NaOH solution were added until a pH 9 wasreached and the aqueous layer was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to provide5-iodo-6-tert-butyl-2-chloroxypyridine-3-carbonitrile (17.35 g, 75%yield) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) ppm 1.55 (s, 9H), 8.38(s, 1H). [M+H]⁺=320.9.

Step 3: 5-Iodo-6-tert-butyl-2-chloropyridine-3-carboxylic acid

Potassium hydroxide (18.2 g, 325 mmol) in water (60 mL) was added to5-iodo-6-tert-butyl-2-chloroxypyridine-3-carbonitrile (17.35 g, 54.1mmol) in 2-propanol (60 mL) and the reaction mixture was heated at 90°C. overnight. Ethyl acetate (50 mL) was added and the organic layer wasextracted with 1 N NaOH (3×50 mL). The basic aqueous layers werecombined and concentrated under reduced pressure to remove most of the2-propanol. The remaining aqueous layer was acidified to pH 1-2 withconcentrated HCl and extracted with ethyl acetate (3×100 mL), Theorganic layers were combined, washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by reverse-phase chromatography(methanol/water, 0% to 100%) to afford5-iodo-6-tert-butyl-2-chloropyridine-3-carboxylic acid (8.2 g, 45%yield) as an off-white solid.¹1-1 NMR (300 MHz, CDCl₃) ppm 1.57 (s, 9H),8.77 (s, 1H). [M+H]⁺=339.9.

Step 4:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-chloro-5-iodo-pyridine-3-carboxamide

To a stirred solution of6-tert-butyl-2-chloro-5-iodo-pyridine-3-carboxylic acid (1.57 g, 4.62mmol) in dry DMF (11.0 mL) added CDI (0.94 g, 5.78 mmol) in one portionunder nitrogen at ambient temperature. The reaction was warmed to 45° C.and stirred for 1.5 h. In a separate flask,6-aminopyridine-2-sulfonamide (1.00 g, 5.78 mmol) was dissolved in dryDMF (9.0 mL) under nitrogen and sodium hydride (60% in mineral oil) (231mg, 5.78 mmol) was added in portions to mitigate gas evolution atambient temperature. The heterogeneous mixture was warmed to 40° C. andstirred for 1 hour. This reaction mixture was added to the stirredactivated acid mixture in one portion at 45° C. Heat was removed and thereaction was stirred for an additional hour. The reaction mixture wasslowly added to ice-cold water (160 mL) then AcOH (1.43 g, 1.35 mL,23.81 mmol) was added and the reaction mixture was stirred vigorouslyfor 10 mins and the solids were filtered and washed with water (3×20mL). The solids were slurried in hexanes (50 mL) and filtered. The solidwas further dried to furnishN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-chloro-5-iodo-pyridine-3-carboxamide(2.11 g, 92%) as white solid.

Step 5:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-iodo-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

To a solution ofN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-chloro-5-iodo-pyridine-3-carboxamide(2.11 g, 4.27 mmol) in anhydrous DMSO (10 mL),(4S)-2,2,4-trimethylpyrrolidine (1.01 g, 8.96 mmol) and K₂CO₃ (2.95 g,21.32 mmol) were added in that order. The reaction mixture was heated at150° C. for 18 h under an atmosphere of nitrogen. The reaction mixturewas allowed to cool to ambient temperature, then poured onto ice-water(125 mL) with stirring. The pH was adjusted to about 6.0 to 7.0 with theaddition of 1 M HCl, the solid was filtered, washed with water (4×20 mL)and dried under vacuum to yieldN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-iodo-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(2.15 g, 88%) as off-white solid.

Step 6:N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-(4-methoxyphenyl)vinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1535)

DMF (0.5 mL) and H₂O (0.1 mL) were added toN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-iodo-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(30 mg, 0.05 mmol) and [(E)-2-(4-methoxyphenyl)vinyl]boronic acid (19mg, 0.11 mmol), followed by K₂CO₃ (29 mg, 0.21 mmol) under an atmosphereof nitrogen. Then tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005mmol) was added, the reaction mixture was sealed under an atmosphere ofnitrogen and heated at 130° C. for 13 h. The reaction mixture wasallowed to cool to ambient temperature and the product was purifiedusing a reverse phase HPLC-MS method using a Luna C18 (2) column (75×30mm, 5 μm particle size) and a dual gradient run from 10-99% mobile phaseB over 30.0 minutes (mobile phase A=H₂O (5 mM HCl), mobile phaseB=CH₃CN) to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-(4-methoxyphenyevinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound 1535) (5 mg, 16%). ESI-MS m/z 578.6 (M+1)⁺; Retention time:1.78 minutes; 1H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.68 (dd,J=8.5, 3.4 Hz 1H), 7.48 (d, J=8.7 Hz, 2H), 7.43 (d, J=15.9 Hz 1H), 7.37(d, J=7.3 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 6.87 (d, J=15.9 Hz, 1H), 6.77(d, J=8.4 Hz, 1H), 3.82 (s, 3H), 3.48 (dd, J=10.9, 8.2 Hz, 1H), 3.17(dd, J=11.1, 9.3 Hz, 1H), 2.69-2.52 (m, 1H), 2.11 (dd, J=12.4, 6.8 Hz,1H), 1.74 (t, J=11.8 Hz, 1H), 1.54 (s, 3H), 1.49 (s, 9H), 1.46 (s, 3H),1.13 (d, J=6.5 Hz, 3H).

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-bicyclo[2.2.1]hept-2-enyl)-6-tert-butyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1577),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-pent-1-enyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1617),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclopropylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1665),-   Ethyl    (E)-3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-3-pyridyl]prop-2-enoate    (Compound 1490),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-5-vinyl-pyridine-3-carboxamide    (Compound 1373) and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-ethoxyvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide    (Compound 1626)

PREPARATION 158:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-phenylbutoxy)pyridine-3-carboxamide(Compound 1686) Step 1:N-((6-amino-2-pyridyl)sulfonyl]-2-fluoro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide

N-[(6-amino-2-pyridyl)sulfonyl]-2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(300 mg, 0.63 mmol) was dissolved in DMSO (1.2 mL). Cesium fluoride (476mg, 3.13 mmol) was added. The reaction mixture was sealed and stirredovernight at 150° C. Additional cesium fluoride (100 mg) was added, andthe reaction mixture was stirred overnight at 150° C. After cooling toroom temperature, the mixture was diluted with EtOAc (75 mL) and washedwith diluted aqueous HCl solution (0.1 N, 1×75 mL). The organic layerwas dried over sodium sulfate, filtered and concentrated under reducedpressure. The product was used in the next step without furtherpurification. ESI-MS m/z 463.2 (M+1)⁺; Retention time: 1.83 minutes.

Step 2:N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-phenylbutoxy)pyridine-3-carboxamide(Compound 1686)

4-phenylbutan-1-ol (23 mg, 0.15 mmol) was dissolved in dioxane (250 μL).Sodium hydride (6 mg, 0.15 mmol) was added, and the reaction mixture wasstirred at room temperature for 5 minutes. A solution ofN-[(6-amino-2-pyridyl)sulfonyl]-2-fluoro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(35 mg, 0.08 mmol) in DMSO (250 μL) was added. After another 5 minutesof stirring, the reaction mixture was heated under microwave irradiationat 100° C. for 30 minutes, then concentrated under reduced pressure andpurified by reverse phase HPLC-MS method using a Luna C18 (2) column(75×30 mm, 5 μm particle size) and a dual gradient run from 1-99% mobilephase B over 15.0 minutes, (mobile phase A=water (5 mM HCl), mobilephase B=acetonitrile) to giveN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-phenylbutoxy)pyridine-3-carboxamide(Compound 1686) (30 mg, 64%). ESI-MS m/z 593.4 (M+1)⁺; Retention time:2.47 minutes.

The following compounds can be synthesized using the proceduresdescribed herein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-phenylbutoxy)pyridine-3-carboxamide    (Compound 1689),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-phenylpropoxy)pyridine-3-carboxamide    (Compound 1694),-   N4(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(3-pyridyl)butoxy]pyridine-3-carboxamide    (Compound 1690),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(4-pyridyl)butoxy]pyridine-3-carboxamide    (Compound 1687),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[4-(2-pyridyl)butoxy]pyridine-3-carboxamide    (Compound 1688),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[3-(2-pyridyl)propoxy]pyridine-3-carboxamide    (Compound 1693),-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[3-(3-pyridyl)propoxy]pyridine-3-carboxamide    (Compound 1691) and-   N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-pyrazol-1-ylpropoxy)pyridine-3-carboxamide    (Compound 1692).

PREPARATION 159:N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-3-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(Compound 1189)

Solid potassium carbonate (90 mg, 0.65 mmol) was added to a suspensionof 2,2-dimethylpyrrolidin-3-one (49 mg, 0.32 mmol) in DMSO (250 μL),followed byN-[(6-amino-2-pyridyl)sulfonyl]-2-fluoro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide(HCl salt) (50 mg, 0.11 mmol). The reaction mixture was stirred at 150°C. for 3 hours. The reaction mixture was purified using a reverse phaseHPLC method using a Luna C18 (2) column (50×21.2 mm, 5 μm particle size)and a dual gradient run from 10-99% mobile phase B over 15.0 minutes(mobile phase A=water (5 mM HCl), mobile phase B=acetonitrile). ESI-MSm/z 556.4 (M+1)⁺; Retention time: 2.01 minutes.

The following compound can be synthesized using the procedures describedherein:

-   N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide    (Compound 1073).

PREPARATION 160:2-(benzenesulfonyl)-1-[5-tert-butyl-2-[(2,4,6-trimethylphenyl)methyl]pyrazol-3-yl]propan-1-one(Compound 139)

To a solution of2-(benzenesulfonyl)-1-{3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazol-5-yl}ethan-1-one(50 mg, 0.11 mmol) in THF (3.0 mL) and DMF (1.0 mL) was added DBU (52mg, 0.34 mmol) and the mixture was stirred at room temperature for 30minutes. Iodomethane (40 mg, 0.28 mmol) was then added and the reactionwas stirred overnight at room temperature. Analysis of an aliquot byLCMS indicated that only mono-methylation (no bis-methylation) hadoccurred. The crude reaction mixture was transferred to a separatoryfunnel with water and extracted twice with diethyl ether. The organiclayers were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give the crude product. In aseparate experiment, a solution of2-(benzenesulfonyl)-1-{3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazol-5-yl}ethan-1-one(50 mg, 0.11 mmol) in THF (3.0 mL) and DMF (1.0 mL) was added DBU (52mg, 0.34 mmol) and the mixture was heated in an oil bath at 80° C. for10 minutes. Iodomethane (40 mg, 0.28 mmol) was then added, the vial wascapped and the reaction was heated in an oil bath at 80° C. overnight.Analysis of an aliquot by LCMS indicated that only mono-methylation (nobis-methylation) had occurred. The crude reaction mixture wastransferred to a separatory funnel with water and extracted twice withdiethyl ether. The organic layers were combined, dried over sodiumsulfate, filtered and concentrated under reduced pressure to give thecrude product. Both crude reaction mixtures were combined together andpurified by silica-gel column chromatography, eluting with 5% to 20%EtOAc in heptanes, to afford rac2-(benzenesulfonyl)-1-{3-tert-butyl-1-[(2,4,6-trimethylphenyl)methyl]-1H-pyrazol-5-ylpropan-1-one(64 mg, 60% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) ppm 1.10(s, 9H), 1.46 (d, J=6.8 Hz, 3H), 2.16 (s, 6H), 2.21 (s, 3H), 5.40-5.53(m, 3H), 6.83 (s, 2H), 7.15 (s, 1H), 7.55-7.62 (m, 2H), 7.68-7.76 (m,3H). ESI-MS m/z 453.2 (M+1)⁺.

Table 2 below recites the analytical data for the compounds of Table 1.

Lengthy table referenced here US20180185364A1-20180705-T00002 Pleaserefer to the end of the specification for access instructions.

Assays

Protocol 1

Assays for Detecting and Measuring F508del Potentiation Properties ofCompounds

Membrane Potential Optical Methods for Assaying F508del ModulationProperties of Compounds

The assay utilizes fluorescent voltage sensing dyes to measure changesin membrane potential using a fluorescent plate reader (e.g., FLIPR III,Molecular Devices, Inc.) as a readout for increase in functional F508delin NIH 3T3 cells. The driving force for the response is the creation ofa chloride ion gradient in conjunction with channel activation by asingle liquid addition step after the cells have previously been treatedwith compounds and subsequently loaded with a voltage sensing dye.

Identification of Potentiator Compounds

To identify potentiators of F508del, a double-addition HTS assay formatwas developed. This HTS assay utilizes fluorescent voltage sensing dyesto measure changes in membrane potential on the FLIPR III as ameasurement for increase in gating (conductance) of F508del intemperature-corrected F508del NIH 3T3 cells. The driving force for theresponse is a Cl⁻ ion gradient in conjunction with channel activationwith forskolin in a single liquid addition step using a fluorescentplate reader such as FLIPR III after the cells have previously beentreated with potentiator compounds (or DMSO vehicle control) andsubsequently loaded with a redistribution dye.

Solutions

Bath Solution #1: (in mM) NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10,_(p)H 7.4 with NaOH.

Chloride-free bath solution: Chloride salts in Bath Solution #1 (above)are substituted with gluconate salts.

Cell Culture

NIH3T3 mouse fibroblasts stably expressing F508del are used for opticalmeasurements of membrane potential. The cells are maintained at 37° C.in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, 13-ME,1×pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For all opticalassays, the cells were seeded at 20,000/well in 384-well matrigel-coatedplates and cultured for 2 hrs at 37° C. before culturing at 27° C. for24 hrs. for the potentiator assay. For the correction assays, the cellsare cultured at 27° C. or 37° C. with and without compounds for 16-24hours.

Electrophysiological Assays for assaying F508del modulation propertiesof compounds.

Ussing Chamber Assay

Ussing chamber experiments were performed on polarized airway epithelialcells expressing F508del to further characterize the F508del augmentersor inducers identified in the optical assays. Non-CF and CF airwayepithelia were isolated from bronchial tissue, cultured as previouslydescribed (Galietta, L. J. V., Lantero, S., Gazzolo, A., Sacco, O.,Romano, L., Rossi, G. A., & Zegarra-Moran, O. (1998) In Vitro Cell. Dev.Biol. 34, 478-481), and plated onto Costar® Snapwell™ filters that wereprecoated with NIH3T3-conditioned media. After four days the apicalmedia was removed and the cells were grown at an air liquid interfacefor >14 days prior to use. This resulted in a monolayer of fullydifferentiated columnar cells that were ciliated, features that arecharacteristic of airway epithelia. Non-CF HBE were isolated fromnon-smokers that did not have any known lung disease. CF-HBE wereisolated from patients homozygous for F508del.

HBE grown on Costar® Snapwell™ cell culture inserts were mounted in anUsing chamber (Physiologic Instruments, Inc., San Diego, Calif.), andthe transepithelial resistance and short-circuit current in the presenceof a basolateral to apical Cl⁻ gradient (I_(sc)) were measured using avoltage-clamp system (Department of Bioengineering, University of Iowa,Iowa). Briefly, HBE were examined under voltage-clamp recordingconditions (V_(hold)=0 mV) at 37° C. The basolateral solution contained(in mM) 145 NaCl, 0.83 K₂HPO₄, 3.3 KHPO₄, 1.2 Mg Cl₂, 1.2 CaCl₂, 10Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apicalsolution contained (in mM) 145 NaGluconate, 1.2 MgCl₂, 1.2 CaCl₂, 10glucose, 10 HEPES (pH adjusted to 7.35 with NaOH).

Identification of Potentiator Compounds

Typical protocol utilized a basolateral to apical membrane CFconcentration gradient. To set up this gradient, normal ringers was usedon the basolateral membrane, whereas apical NaCl was replaced byequimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give alarge Cl⁻ concentration gradient across the epithelium. Forskolin (10μM) and all test compounds were added to the apical side of the cellculture inserts. The efficacy of the putative F508del potentiators wascompared to that of the known potentiator, genistein.

Patch-Clamp Recordings

Total Cl⁻ current in F508del-NIH3T3 cells was monitored using theperforated-patch recording configuration as previously described (Rae,J., Cooper, K., Gates, P., & Watsky, M. (1991) J. Neurosci. Methods 37,15-26). Voltage-clamp recordings were performed at 22° C. using anAxopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City,Calif.). The pipette solution contained (in mM) 150 N-methyl-D-glucamine(NMDG)-Cl, 2 MgCl₂, 2 CaCl₂, 10 EGTA, 10 HEPES, and 240 μg/mLamphotericin-B (pH adjusted to 7.35 with HCl). The extracellular mediumcontained (in mM) 150 NMDG-Cl, 2 MgCl₂, 2 CaCl₂, 10 HEPES (pH adjustedto 7.35 with HCl). Pulse generation, data acquisition, and analysis wereperformed using a PC equipped with a Digidata 1320 A/D interface inconjunction with Clampex 8 (Axon Instruments Inc.). To activate F508del,10 μM forskolin and 20 μM genistein were added to the bath and thecurrent-voltage relation was monitored every 30 sec.

Identification of Potentiator Compounds

The ability of F508del potentiators to increase the macroscopic F508delCl⁻ current (I_(F508del)) in NIH3T3 cells stably expressing F508del wasalso investigated using perforated-patch-recording techniques. Thepotentiators identified from the optical assays evoked a dose-dependentincrease in IΔ_(F508) with similar potency and efficacy observed in theoptical assays. In all cells examined, the reversal potential before andduring potentiator application was around −30 mV, which is thecalculated E_(Cl) (−28 mV).

Cell Culture

NIH3T3 mouse fibroblasts stably expressing F508del are used forwhole-cell recordings. The cells are maintained at 37° C. in 5% CO²) and90% humidity in Dulbecco's modified Eagle's medium supplemented with 2mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME, 1×pen/strep, and 25mM HEPES in 175 cm² culture flasks. For whole-cell recordings,2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslipsand cultured for 24-48 hrs at 27° C. before use to test the activity ofpotentiators; and incubated with or without the correction compound at37° C. for measuring the activity of correctors.

Single-Channel Recordings

Gating activity of wt-CFTR and temperature-corrected F508del expressedin NIH3T3 cells was observed using excised inside-out membrane patchrecordings as previously described (Dalemans, W., Barbry, P., Champigny,G., Jallat, S., Dott, K., Dreyer, D., Crystal, R. G., Pavirani, A.,Lecocq, J-P., Lazdunski, M. (1991) Nature 354, 526-528) using anAxopatch 200B patch-clamp amplifier (Axon Instruments Inc.). The pipettecontained (in mM): 150 NMDG, 150 aspartic acid, 5 CaCl₂, 2 MgCl₂, and 10HEPES (pH adjusted to 7.35 with Tris base). The bath contained (in mM):150 NMDG-Cl, 2 MgCl₂, 5 EGTA, 10 TES, and 14 Tris base (pH adjusted to7.35 with HCl). After excision, both wt- and F508del were activated byadding 1 mM Mg-ATP, 75 nM of the catalytic subunit of cAMP-dependentprotein kinase (PKA; Promega Corp. Madison, Wis.), and 10 mM NaF toinhibit protein phosphatases, which prevented current rundown. Thepipette potential was maintained at 80 mV. Channel activity was analyzedfrom membrane patches containing ≤2 active channels. The maximum numberof simultaneous openings determined the number of active channels duringthe course of an experiment. To determine the single-channel currentamplitude, the data recorded from 120 sec of F508del activity wasfiltered “off-line” at 100 Hz and then used to construct all-pointamplitude histograms that were fitted with multigaussian functions usingBio-Patch Analysis software (Bio-Logic Comp. France). The totalmicroscopic current and open probability (P_(o)) were determined from120 sec of channel activity. The P_(o) was determined using theBio-Patch software or from the relationship P_(o)=I/i(N), where I=meancurrent, i=single-channel current amplitude, and N=number of activechannels in patch.

Cell Culture

NIH3T3 mouse fibroblasts stably expressing F508del are used forexcised-membrane patch-clamp recordings. The cells are maintained at 37°C. in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1×pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For singlechannel recordings, 2,500-5,000 cells were seeded onpoly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27°C. before use.

Protocol 2

Assays for Detecting and Measuring F508del Correction Properties ofCompounds

Membrane potential optical methods for assaying F508del modulationproperties of compounds.

The optical membrane potential assay utilized voltage-sensitive FRETsensors described by Gonzalez and Tsien (See Gonzalez, J. E. and R. Y.Tsien (1995) “Voltage sensing by fluorescence resonance energy transferin single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

These voltage sensitive assays are based on the change in fluorescenceresonant energy transfer (FRET) between the membrane-soluble,voltage-sensitive dye, DiSBAC₂(3), and a fluorescent phospholipid,CC2-DMPE, which is attached to the outer leaflet of the plasma membraneand acts as a FRET donor. Changes in membrane potential (V_(m)) causethe negatively charged DiSBAC₂(3) to redistribute across the plasmamembrane and the amount of energy transfer from CC2-DMPE changesaccordingly. The changes in fluorescence emission were monitored usingVIPR™ II, which is an integrated liquid handler and fluorescent detectordesigned to conduct cell-based screens in 96- or 384-well microtiterplates.

Identification of Correction Compounds

To identify small molecules that correct the trafficking defectassociated with F508del; a single-addition HTS assay format wasdeveloped. The cells were incubated in serum-free medium for 16 hrs at37° C. in the presence or absence (negative control) of test compound.As a positive control, cells plated in 384-well plates were incubatedfor 16 hrs at 27° C. to “temperature-correct” F508del. The cells weresubsequently rinsed 3× with Krebs Ringers solution and loaded with thevoltage-sensitive dyes. To activate F508del, 10 μM forskolin and theCFTR potentiator, genistein (20 μM), were added along with CF-freemedium to each well. The addition of CF-free medium promoted Cl⁻ effluxin response to F508del activation and the resulting membranedepolarization was optically monitored using the FRET-basedvoltage-sensor dyes.

Identification of Potentiator Compounds

To identify potentiators of F508del, a double-addition HTS assay formatwas developed. During the first addition, a CF-free medium with orwithout test compound was added to each well. After 22 sec, a secondaddition of Cl⁻-free medium containing 2-10 μM forskolin was added toactivate F508del. The extracellular Cl⁻ concentration following bothadditions was 28 mM, which promoted Cl⁻ efflux in response to F508delactivation and the resulting membrane depolarization was opticallymonitored using the FRET-based voltage-sensor dyes.

Solutions

-   -   Bath Solution #1: (in mM) NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1,        HEPES 10, pH 7.4 with NaOH.    -   Chloride-free bath solution: Chloride salts in Bath Solution #1        (above) are substituted with gluconate salts.    -   CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored        at −20° C.    -   DiSBAC₂(3): Prepared as a 10 mM stock in DMSO and stored at −20°        C.

Cell Culture

NIH3T3 mouse fibroblasts stably expressing F508del are used for opticalmeasurements of membrane potential. The cells are maintained at 37° C.in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1× pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For all opticalassays, the cells were seeded at 30,000/well in 384-well matrigel-coatedplates and cultured for 2 hrs at 37° C. before culturing at 27° C. for24 hrs for the potentiator assay. For the correction assays, the cellsare cultured at 27° C. or 37° C. with and without compounds for 16-24hours.

Electrophysiological Assays for assaying F508del modulation propertiesof compounds

Using Chamber Assay

Using chamber experiments were performed on polarized epithelial cellsexpressing F508del to further characterize the F508del augmenters orinducers identified in the optical assays. FRT^(F508del) epithelialcells grown on Costar Snapwell cell culture inserts were mounted in anUssing chamber (Physiologic Instruments, Inc., San Diego, Calif.), andthe monolayers were continuously short-circuited using a Voltage-clampSystem (Department of Bioengineering, University of Iowa, Iowa, and,Physiologic Instruments, Inc., San Diego, Calif.). Transepithelialresistance was measured by applying a 2-mV pulse. Under theseconditions, the FRT epithelia demonstrated resistances of 4 KΩ/cm² ormore. The solutions were maintained at 27° C. and bubbled with air. Theelectrode offset potential and fluid resistance were corrected using acell-free insert. Under these conditions, the current reflects the flowof Cl⁻ through F508del expressed in the apical membrane. The I_(SC) wasdigitally acquired using an MP100A-CE interface and AcqKnowledgesoftware (v3.2.6; BIOPAC Systems, Santa Barbara, Calif.).

Identification of Correction Compounds

Typical protocol utilized a basolateral to apical membrane CFconcentration gradient. To set up this gradient, normal ringer was usedon the basolateral membrane, whereas apical NaCl was replaced byequimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give alarge Cl⁻ concentration gradient across the epithelium. All experimentswere performed with intact monolayers. To fully activate F508del,forskolin (10 μM) and the PDE inhibitor, IBMX (100 μM), were appliedfollowed by the addition of the CFTR potentiator, genistein (50 μM).

As observed in other cell types, incubation at low temperatures of FRTcells stably expressing F508del increases the functional density of CFTRin the plasma membrane. To determine the activity of correctioncompounds, the cells were incubated with 10 μM of the test compound for24 hours at 37° C. and were subsequently washed 3× prior to recording.The cAMP- and genistein-mediated I_(SC) in compound-treated cells wasnormalized to the 27° C. and 37° C. controls and expressed as percentageactivity. Preincubation of the cells with the correction compoundsignificantly increased the cAMP- and genistein-mediated I_(SC) comparedto the 37° C. controls.

Identification of Potentiator Compounds

Typical protocol utilized a basolateral to apical membrane Cl⁻concentration gradient. To set up this gradient, normal ringers was usedon the basolateral membrane and was permeabilized with nystatin (360μg/ml), whereas apical NaCl was replaced by equimolar sodium gluconate(titrated to pH 7.4 with NaOH) to give a large Cl⁻ concentrationgradient across the epithelium. All experiments were performed 30 minafter nystatin permeabilization. Forskolin (10 μM) and all testcompounds were added to both sides of the cell culture inserts. Theefficacy of the putative F508del potentiators was compared to that ofthe known potentiator, genistein.

Solutions

-   -   Basolateral solution (in mM): NaCl (135), CaCl₂ (1.2), MgCl₂        (1.2), K₂HPO₄ (2.4), KHPO₄ (0.6),        N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)        (10), and dextrose (10). The solution was titrated to pH 7.4        with NaOH.    -   Apical solution (in mM): Same as basolateral solution with NaCl        replaced with Na Gluconate (135).

Cell Culture

Fisher rat epithelial (FRT) cells expressing F508del (FRT^(F508del))wereused for Ussing chamber experiments for the putative F508del augmentersor inducers identified from our optical assays. The cells were culturedon Costar Snapwell cell culture inserts and cultured for five days at37° C. and 5% CO₂ in Coon's modified Ham's F-12 medium supplemented with5% fetal calf serum, 100 U/ml penicillin, and 100 μg/ml streptomycin.Prior to use for characterizing the potentiator activity of compounds,the cells were incubated at 27° C. for 16-48 hrs to correct for theF508del. To determine the activity of corrections compounds, the cellswere incubated at 27° C. or 37° C. with and without the compounds for 24hours.

Whole-Cell Recordings

The macroscopic F508del current (I_(F508del)) in temperature- and testcompound-corrected NIH3T3 cells stably expressing F_(508del) weremonitored using the perforated-patch, whole-cell recording. Briefly,voltage-clamp recordings of _(IF508de1) were performed at roomtemperature using an Axopatch 200B patch-clamp amplifier (AxonInstruments Inc., Foster City, Calif.). All recordings were acquired ata sampling frequency of 10 kHz and low-pass filtered at 1 kHz. Pipetteshad a resistance of 5-6 MΩ when filled with the intracellular solution.Under these recording conditions, the calculated reversal potential forCl⁻ (E_(Cl)) at room temperature was −28 mV. All recordings had a sealresistance >20 GΩ and a series resistance <15 MΩ. Pulse generation, dataacquisition, and analysis were performed using a PC equipped with aDigidata 1320 A/D interface in conjunction with Clampex 8 (AxonInstruments Inc.). The bath contained <250 μl of saline and wascontinuously perifused at a rate of 2 ml/min using a gravity-drivenperfusion system.

Identification of Correction Compounds

To determine the activity of correction compounds for increasing thedensity of functional F508del in the plasma membrane, we used theabove-described perforated-patch-recording techniques to measure thecurrent density following 24-hr treatment with the correction compounds.To fully activate F508del, 10 μM forskolin and 20 μM genistein wereadded to the cells. Under our recording conditions, the current densityfollowing 24-hr incubation at 27° C. was higher than that observedfollowing 24-hr incubation at 37° C. These results are consistent withthe known effects of low-temperature incubation on the density ofF508del in the plasma membrane. To determine the effects of correctioncompounds on CFTR current density, the cells were incubated with 10 μMof the test compound for 24 hours at 37° C. and the current density wascompared to the 27° C. and 37° C. controls (% activity). Prior torecording, the cells were washed 3× with extracellular recording mediumto remove any remaining test compound. Preincubation with 10 μM ofcorrection compounds significantly increased the cAMP- andgenistein-dependent current compared to the 37° C. controls.

Identification of Potentiator Compounds

The ability of F508del potentiators to increase the macroscopic F508delCl⁻ current (I_(F508del)) in NIH3T3 cells stably expressing F508del wasalso investigated using perforated-patch-recording techniques. Thepotentiators identified from the optical assays evoked a dose-dependentincrease in I_(F508del) with similar potency and efficacy observed inthe optical assays. In all cells examined, the reversal potential beforeand during potentiator application was around −30 mV, which is thecalculated E_(Cl) (−28 mV).

Solutions

-   -   Intracellular solution (in mM): Cs-aspartate (90), CsCl (50),        MgCl₂ (1),

HEPES (10), and 240 μg/ml amphotericin-B (pH adjusted to 7.35 withCsOH).

-   -   Extracellular solution (in mM): N-methyl-D-glucamine (NMDG)-Cl        (150), MgCl₂ (2), CaCl₂ (2), HEPES (10) (pH adjusted to 7.35        with HCI).

Cell Culture

NIH3T3 mouse fibroblasts stably expressing F508del are used forwhole-cell recordings. The cells are maintained at 37° C. in 5% CO₂) and90% humidity in Dulbecco's modified Eagle's medium supplemented with 2mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME, 1×pen/strep, and 25mM HEPES in 175 cm² culture flasks. For whole-cell recordings,2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslipsand cultured for 24-48 hrs at 27° C. before use to test the activity ofpotentiators; and incubated with or without the correction compound at37° C. for measuring the activity of correctors.

Single-Channel Recordings

The single-channel activities of temperature-corrected F508del stablyexpressed in NIH3T3 cells and activities of potentiator compounds wereobserved using excised inside-out membrane patch. Briefly, voltage-clamprecordings of single-channel activity were performed at room temperaturewith an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). Allrecordings were acquired at a sampling frequency of 10 kHz and low-passfiltered at 400 Hz. Patch pipettes were fabricated from Corning KovarSealing #7052 glass (World Precision Instruments, Inc., Sarasota, Fla.)and had a resistance of 5-8 MΩ when filled with the extracellularsolution. The F508del was activated after excision, by adding 1 mMMg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalyticsubunit (PKA; Promega Corp. Madison, Wis.). After channel activitystabilized, the patch was perifused using a gravity-drivenmicroperfusion system. The inflow was placed adjacent to the patch,resulting in complete solution exchange within 1-2 sec. To maintainF508del activity during the rapid perifusion, the nonspecificphosphatase inhibitor F (10 mM NaF) was added to the bath solution.Under these recording conditions, channel activity remained constantthroughout the duration of the patch recording (up to 60 min). Currentsproduced by positive charge moving from the intra- to extracellularsolutions (anions moving in the opposite direction) are shown aspositive currents. The pipette potential (V_(p)) was maintained at 80mV.

Channel activity was analyzed from membrane patches containing ≤2 activechannels. The maximum number of simultaneous openings determined thenumber of active channels during the course of an experiment. Todetermine the single-channel current amplitude, the data recorded from120 sec of F508del activity was filtered “off-line” at 100 Hz and thenused to construct all-point amplitude histograms that were fitted withmultigaussian functions using Bio-Patch Analysis software (Bio-LogicComp. France). The total microscopic current and open probability(P_(o)) were determined from 120 sec of channel activity. The P_(o) wasdetermined using the Bio-Patch software or from the relationshipP_(o)=I/i(N), where I=mean current, i=single-channel current amplitude,and N=number of active channels in patch.

Solutions

-   -   Extracellular solution (in mM): NMDG (150), aspartic acid (150),        CaCl₂ (5), MgCl₂ (2), and HEPES (10) (pH adjusted to 7.35 with        Tris base).    -   Intracellular solution (in mM): NMDG-Cl (150), MgCl₂ (2), EGTA        (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with        HCl).

Cell Culture

NIH3T3 mouse fibroblasts stably expressing F508del are used forexcised-membrane patch-clamp recordings. The cells are maintained at 37°C. in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1×pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For singlechannel recordings, 2,500-5,000 cells were seeded onpoly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27°C. before use.

The compounds of formula I are useful as modulators of CFTR activity.Table 3 below illustrates the EC30 and relative efficacy of thecompounds of Table 1. In Table 3 below, the following meanings apply.EC30: “+++” means <3 uM; “++” means between 3 uM and 10 uM; “+” meansgreater than 10 uM.

TABLE 3 Cmpd. EC30 No. (μM) 1 +++ 2 +++ 3 +++ 4 + 5 ++ 6 +++ 7 +++ 8 +++9 +++ 10 +++ 11 +++ 12 +++ 13 ++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19+++ 20 +++ 21 +++ 22 +++ 23 ++ 24 ++ 25 ++ 26 ++ 27 +++ 28 +++ 29 +++ 30+++ 31 ++ 32 ++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 ++ 40 +++41 +++ 42 ++ 43 +++ 44 ++ 45 +++ 46 ++ 47 +++ 48 ++ 49 +++ 50 +++ 51 +++52 +++ 53 +++ 54 ++ 55 ++ 56 +++ 57 +++ 58 ++ 59 +++ 60 +++ 61 +++ 62+++ 63 +++ 64 ++ 65 ++ 66 +++ 67 ++ 68 +++ 69 +++ 70 +++ 71 +++ 72 ++ 73+++ 74 +++ 75 ++ 76 +++ 77 +++ 78 +++ 79 ++ 80 +++ 81 +++ 82 +++ 83 +++84 +++ 85 ++ 86 ++ 87 +++ 88 +++ 89 +++ 90 +++ 91 ++ 92 +++ 93 +++ 94+++ 95 +++ 96 +++ 97 +++ 98 +++ 99 +++ 100 +++ 101 +++ 102 +++ 103 +++104 +++ 105 +++ 106 +++ 107 +++ 108 +++ 109 +++ 110 +++ 111 +++ 112 +++113 ++ 114 +++ 115 +++ 116 ++ 117 +++ 118 ++ 119 +++ 120 +++ 121 ++ 122++ 123 +++ 124 ++ 125 ++ 126 +++ 127 +++ 128 +++ 129 ++ 130 +++ 131 +++132 +++ 133 +++ 134 +++ 135 +++ 136 +++ 137 +++ 138 ++ 139 +++ 140 +++141 +++ 142 +++ 143 +++ 144 +++ 145 +++ 146 +++ 147 +++ 148 +++ 149 +++150 +++ 151 +++ 152 +++ 153 +++ 154 +++ 155 ++ 156 +++ 157 ++ 158 +++159 +++ 160 +++ 161 +++ 162 +++ 163 +++ 164 +++ 165 +++ 166 +++ 167 ++168 +++ 169 +++ 170 +++ 171 +++ 172 +++ 173 ++ 174 ++ 175 ++ 176 +++ 177++ 178 +++ 179 +++ 180 +++ 181 +++ 182 +++ 183 +++ 184 ++ 185 +++ 186+++ 187 ++ 188 +++ 189 +++ 190 +++ 191 +++ 192 +++ 193 +++ 194 +++ 195+++ 196 +++ 197 +++ 198 +++ 199 +++ 200 ++ 201 +++ 202 +++ 203 +++ 204+++ 205 ++ 206 +++ 207 +++ 208 +++ 209 +++ 210 +++ 211 ++ 212 +++ 213+++ 214 +++ 215 +++ 216 +++ 217 +++ 218 ++ 219 +++ 220 +++ 221 +++ 222+++ 223 +++ 224 +++ 225 +++ 226 +++ 227 ++ 228 +++ 229 +++ 230 ++ 231+++ 232 +++ 233 +++ 234 +++ 235 +++ 236 ++ 237 ++ 238 +++ 239 +++ 240 ++241 +++ 242 +++ 243 +++ 244 +++ 245 ++ 246 ++ 247 +++ 248 +++ 249 +++250 +++ 251 +++ 252 +++ 253 +++ 254 ++ 255 +++ 256 +++ 257 +++ 258 ++259 +++ 260 ++ 261 +++ 262 +++ 263 +++ 264 +++ 265 +++ 266 +++ 267 +++268 +++ 269 +++ 270 +++ 271 +++ 272 ++ 273 +++ 274 +++ 275 +++ 276 +++277 +++ 278 ++ 279 +++ 280 +++ 281 +++ 282 ++ 283 +++ 284 +++ 285 +++286 +++ 287 +++ 288 +++ 289 +++ 290 +++ 291 ++ 292 +++ 293 +++ 294 +++295 ++ 296 +++ 297 ++ 298 ++ 299 +++ 300 +++ 301 ++ 302 ++ 303 +++ 304+++ 305 +++ 306 +++ 307 +++ 308 +++ 309 +++ 310 +++ 311 +++ 312 +++ 313+++ 314 +++ 315 +++ 316 +++ 317 +++ 318 +++ 319 ++ 320 +++ 321 +++ 322+++ 323 +++ 324 ++ 325 +++ 326 +++ 327 +++ 328 +++ 329 +++ 330 +++ 331+++ 332 +++ 333 +++ 334 ++ 335 +++ 336 +++ 337 +++ 338 +++ 339 +++ 340+++ 341 +++ 342 +++ 343 +++ 344 +++ 345 +++ 346 +++ 347 +++ 348 +++ 349++ 350 +++ 351 +++ 352 +++ 353 +++ 354 +++ 355 +++ 356 +++ 357 ++ 358+++ 359 +++ 360 +++ 361 +++ 362 +++ 363 +++ 364 +++ 365 +++ 366 +++ 367+++ 368 +++ 369 +++ 370 +++ 371 +++ 372 ++ 373 ++ 374 +++ 375 +++ 376+++ 377 +++ 378 +++ 379 +++ 380 +++ 381 ++ 382 +++ 383 +++ 384 +++ 385+++ 386 +++ 387 +++ 388 ++ 389 +++ 390 +++ 391 + 392 ++ 393 ++ 394 +++395 +++ 396 +++ 397 +++ 398 +++ 399 +++ 400 ++ 401 +++ 402 +++ 403 ++404 +++ 405 +++ 406 +++ 407 ++ 408 +++ 409 + 410 +++ 411 +++ 412 +++ 413+++ 414 +++ 415 +++ 416 +++ 417 ++ 418 +++ 419 +++ 420 +++ 421 +++ 422+++ 423 +++ 424 +++ 425 +++ 426 +++ 427 +++ 428 +++ 429 +++ 430 +++ 431++ 432 +++ 433 +++ 434 +++ 435 +++ 436 +++ 437 +++ 438 +++ 439 +++ 440+++ 441 +++ 442 +++ 443 + 444 ++ 445 + 446 +++ 447 +++ 448 +++ 449 + 450+++ 451 ++ 452 +++ 453 +++ 454 +++ 455 +++ 456 +++ 457 +++ 458 +++ 459+++ 460 ++ 461 ++ 462 +++ 463 ++ 464 +++ 465 ++ 466 +++ 467 ++ 468 +++469 ++ 470 +++ 471 +++ 472 + 473 +++ 474 +++ 475 +++ 476 ++ 477 +++ 478++ 479 +++ 480 +++ 481 +++ 482 +++ 483 +++ 484 485 +++ 486 ++ 487 ++ 488+++ 489 +++ 490 +++ 491 +++ 492 +++ 493 +++ 494 +++ 495 ++ 496 +++ 497+++ 498 +++ 499 ++ 500 +++ 501 +++ 502 +++ 503 +++ 504 +++ 505 ++ 506+++ 507 +++ 508 ++ 509 +++ 510 +++ 511 +++ 512 ++ 513 ++ 514 + 515 +++516 +++ 517 ++ 518 +++ 519 ++ 520 +++ 521 ++ 522 +++ 523 +++ 524 ++ 525++ 526 +++ 527 +++ 528 +++ 529 ++ 530 +++ 531 +++ 532 ++ 533 +++ 534 ++535 +++ 536 +++ 537 +++ 538 +++ 539 + 540 + 541 +++ 542 +++ 543 ++ 544+++ 545 ++ 546 ++ 547 +++ 548 +++ 549 +++ 550 ++ 551 +++ 552 ++ 553 +++554 +++ 555 +++ 556 + 557 +++ 558 +++ 559 +++ 560 +++ 561 +++ 562 +++563 +++ 564 ++ 565 + 566 + 567 ++ 568 +++ 569 +++ 570 +++ 571 ++ 572 +++573 +++ 574 ++ 575 +++ 576 +++ 577 ++ 578 +++ 579 +++ 580 +++ 581 +++582 ++ 583 +++ 584 ++ 585 +++ 586 +++ 587 +++ 588 ++ 589 +++ 590 +++ 591+++ 592 +++ 593 +++ 594 ++ 595 +++ 596 ++ 597 +++ 598 ++ 599 +++ 600 +++601 +++ 602 +++ 603 +++ 604 +++ 605 +++ 606 ++ 607 +++ 608 ++ 609 +++610 +++ 611 +++ 612 +++ 613 +++ 614 +++ 615 +++ 616 +++ 617 +++ 618 ++619 +++ 620 +++ 621 +++ 622 +++ 623 ++ 624 ++ 625 +++ 626 +++ 627 + 628+++ 629 +++ 630 +++ 631 +++ 632 ++ 633 +++ 634 +++ 635 + 636 ++ 637 ++638 ++ 639 +++ 640 ++ 641 +++ 642 +++ 643 ++ 644 +++ 645 ++ 646 ++ 647+++ 648 +++ 649 ++ 650 ++ 651 +++ 652 ++ 653 + 654 +++ 655 +++ 656 +++657 +++ 658 +++ 659 ++ 660 + 661 +++ 662 + 663 +++ 664 +++ 665 +++ 666++ 667 +++ 668 +++ 669 +++ 670 ++ 671 +++ 672 +++ 673 +++ 674 +++ 675+++ 676 +++ 677 ++ 678 +++ 679 +++ 680 +++ 681 +++ 682 +++ 683 +++ 684+++ 685 +++ 686 +++ 687 ++ 688 +++ 689 +++ 690 ++ 691 +++ 692 +++ 693+++ 694 +++ 695 +++ 696 +++ 697 +++ 698 699 +++ 700 +++ 701 +++ 702 ++703 +++ 704 ++ 705 +++ 706 +++ 707 + 708 +++ 709 +++ 710 +++ 711 +++ 712+++ 713 ++ 714 +++ 715 +++ 716 +++ 717 +++ 718 +++ 719 +++ 720 +++ 721++ 722 + 723 ++ 724 +++ 725 +++ 726 ++ 727 + 728 ++ 729 ++ 730 +++ 731+++ 732 +++ 733 +++ 734 +++ 735 +++ 736 +++ 737 +++ 738 +++ 739 ++ 740++ 741 +++ 742 +++ 743 +++ 744 +++ 745 ++ 746 +++ 747 +++ 748 ++ 749 +++750 +++ 751 +++ 752 ++ 753 ++ 754 +++ 755 ++ 756 +++ 757 +++ 758 ++ 759+++ 760 ++ 761 +++ 762 ++ 763 +++ 764 +++ 765 ++ 766 ++ 767 +++ 768 ++769 +++ 770 ++ 771 +++ 772 +++ 773 +++ 774 +++ 775 +++ 776 +++ 777 +++778 +++ 779 +++ 780 +++ 781 + 782 +++ 783 +++ 784 +++ 785 +++ 786 + 787+++ 788 +++ 789 +++ 790 +++ 791 ++ 792 ++ 793 +++ 794 +++ 795 +++ 796+++ 797 + 798 +++ 799 + 800 ++ 801 + 802 +++ 803 +++ 804 +++ 805 +++ 806++ 807 +++ 808 ++ 809 ++ 810 ++ 811 +++ 812 ++ 813 +++ 814 +++ 815 ++816 ++ 817 +++ 818 +++ 819 + 820 + 821 ++ 822 +++ 823 + 824 ++ 825 ++826 +++ 827 +++ 828 +++ 829 +++ 830 +++ 831 +++ 832 +++ 833 +++ 834 +++835 ++ 836 ++ 837 +++ 838 ++ 839 ++ 840 +++ 841 +++ 842 +++ 843 ++ 844++ 845 +++ 846 +++ 847 +++ 848 +++ 849 + 850 +++ 851 +++ 852 ++ 853 +++854 ++ 855 + 856 ++ 857 +++ 858 ++ 859 +++ 860 ++ 861 ++ 862 +++ 863 ++864 +++ 865 +++ 866 +++ 867 +++ 868 +++ 869 +++ 870 ++ 871 +++ 872 ++873 +++ 874 +++ 875 +++ 876 +++ 877 +++ 878 ++ 879 + 880 ++ 881 +++ 882+++ 883 ++ 884 ++ 885 ++ 886 +++ 887 +++ 888 ++ 889 ++ 890 +++ 891 +++892 ++ 893 +++ 894 +++ 895 +++ 896 +++ 897 +++ 898 +++ 899 +++ 900 +++901 ++ 902 +++ 903 ++ 904 +++ 905 +++ 906 +++ 907 +++ 908 + 909 +++ 910+++ 911 +++ 912 +++ 913 ++ 914 +++ 915 +++ 916 +++ 917 ++ 918 +++ 919+++ 920 +++ 921 ++ 922 +++ 923 +++ 924 +++ 925 +++ 926 +++ 927 ++ 928+++ 929 ++ 930 ++ 931 +++ 932 + 933 +++ 934 +++ 935 ++ 936 ++ 937 +++938 ++ 939 +++ 940 +++ 941 +++ 942 +++ 943 + 944 +++ 945 +++ 946 ++ 947+++ 948 +++ 949 +++ 950 +++ 951 +++ 952 +++ 953 +++ 954 +++ 955 ++ 956+++ 957 +++ 958 +++ 959 +++ 960 ++ 961 +++ 962 ++ 963 ++ 964 +++ 965 +++966 + 967 +++ 968 +++ 969 +++ 970 971 +++ 972 +++ 973 +++ 974 +++ 975 ++976 ++ 977 ++ 978 +++ 979 +++ 980 ++ 981 ++ 982 ++ 983 ++ 984 +++ 985+++ 986 ++ 987 +++ 988 +++ 989 +++ 990 +++ 991 +++ 992 +++ 993 +++ 994+++ 995 +++ 996 +++ 997 ++ 998 ++ 999 ++ 1000 +++ 1001 ++ 1002 +++1003 + 1004 +++ 1005 +++ 1006 +++ 1007 +++ 1008 +++ 1009 +++ 1010 +++1011 +++ 1012 +++ 1013 +++ 1014 +++ 1015 +++ 1016 +++ 1017 ++ 1018 ++1019 +++ 1020 +++ 1021 +++ 1022 ++ 1023 +++ 1024 ++ 1025 +++ 1026 ++1027 ++ 1028 ++ 1029 ++ 1030 +++ 1031 +++ 1032 +++ 1033 +++ 1034 +++1035 +++ 1036 + 1037 ++ 1038 ++ 1039 +++ 1040 +++ 1041 +++ 1042 +++ 1043+++ 1044 +++ 1045 ++ 1046 ++ 1047 +++ 1048 +++ 1049 +++ 1050 ++ 1051 +++1052 +++ 1053 ++ 1054 +++ 1055 ++ 1056 +++ 1057 + 1058 +++ 1059 +++ 1060+++ 1061 +++ 1062 +++ 1063 +++ 1064 +++ 1065 +++ 1066 ++ 1067 +++ 1068+++ 1069 +++ 1070 +++ 1071 +++ 1072 ++ 1073 + 1074 ++ 1075 +++ 1076 +++1077 +++ 1078 ++ 1079 +++ 1080 +++ 1081 ++ 1082 + 1083 +++ 1084 ++ 1085+++ 1086 ++ 1087 +++ 1088 +++ 1089 +++ 1090 +++ 1091 +++ 1092 ++ 1093 ++1094 +++ 1095 ++ 1096 ++ 1097 +++ 1098 +++ 1099 +++ 1100 +++ 1101 +++1102 +++ 1103 +++ 1104 +++ 1105 + 1106 + 1107 +++ 1108 +++ 1109 ++ 1110+++ 1111 +++ 1112 ++ 1113 +++ 1114 1115 + 1116 ++ 1117 +++ 1118 +++ 1119++ 1120 +++ 1121 +++ 1122 ++ 1123 +++ 1124 +++ 1125 ++ 1126 + 1127 +++1128 ++ 1129 ++ 1130 ++ 1131 +++ 1132 +++ 1133 +++ 1134 +++ 1135 +++1136 +++ 1137 ++ 1138 +++ 1139 +++ 1140 +++ 1141 ++ 1142 ++ 1143 ++ 1144+++ 1145 +++ 1146 ++ 1147 ++ 1148 +++ 1149 +++ 1150 +++ 1151 ++ 1152 +1153 +++ 1154 ++ 1155 ++ 1156 +++ 1157 +++ 1158 +++ 1159 +++ 1160 +++1161 +++ 1162 +++ 1163 +++ 1164 ++ 1165 ++ 1166 +++ 1167 +++ 1168 +++1169 ++ 1170 +++ 1171 +++ 1172 ++ 1173 +++ 1174 +++ 1175 +++ 1176 +++1177 ++ 1178 +++ 1179 ++ 1180 +++ 1181 +++ 1182 ++ 1183 + 1184 +++ 1185+++ 1186 +++ 1187 +++ 1188 +++ 1189 +++ 1190 +++ 1191 ++ 1192 +++ 1193+++ 1194 +++ 1195 + 1196 ++ 1197 +++ 1198 +++ 1199 ++ 1200 ++ 1201 +++1202 +++ 1203 + 1204 + 1205 +++ 1206 ++ 1207 +++ 1208 +++ 1209 +++ 1210+++ 1211 ++ 1212 +++ 1213 ++ 1214 ++ 1215 ++ 1216 +++ 1217 + 1218 +++1219 ++ 1220 +++ 1221 +++ 1222 +++ 1223 +++ 1224 ++ 1225 +++ 1226 +++1227 +++ 1228 ++ 1229 +++ 1230 ++ 1231 +++ 1232 +++ 1233 ++ 1234 +++1235 +++ 1236 ++ 1237 ++ 1238 +++ 1239 +++ 1240 +++ 1241 +++ 1242 +++1243 +++ 1244 +++ 1245 + 1246 +++ 1247 +++ 1248 +++ 1249 +++ 1250 +++1251 ++ 1252 +++ 1253 ++ 1254 +++ 1255 +++ 1256 ++ 1257 ++ 1258 +++ 1259+++ 1260 +++ 1261 +++ 1262 ++ 1263 +++ 1264 +++ 1265 ++ 1266 +++ 1267+++ 1268 +++ 1269 +++ 1270 +++ 1271 +++ 1272 +++ 1273 +++ 1274 +++ 1275+++ 1276 ++ 1277 +++ 1278 + 1279 +++ 1280 +++ 1281 ++ 1282 +++ 1283 +++1284 +++ 1285 +++ 1286 +++ 1287 +++ 1288 ++ 1289 +++ 1290 +++ 1291 ++1292 + 1293 ++ 1294 +++ 1295 +++ 1296 + 1297 +++ 1298 ++ 1299 ++ 1300+++ 1301 ++ 1302 ++ 1303 +++ 1304 +++ 1305 +++ 1306 +++ 1307 ++ 1308 +++1309 +++ 1310 +++ 1311 +++ 1312 ++ 1313 +++ 1314 +++ 1315 +++ 1316 +++1317 +++ 1318 +++ 1319 +++ 1320 +++ 1321 ++ 1322 ++ 1323 + 1324 +++ 1325+++ 1326 ++ 1327 +++ 1328 +++ 1329 ++ 1330 +++ 1331 + 1332 +++ 1333 +++1334 +++ 1335 +++ 1336 +++ 1337 +++ 1338 ++ 1339 +++ 1340 +++ 1341 +++1342 +++ 1343 +++ 1344 ++ 1345 +++ 1346 +++ 1347 +++ 1348 +++ 1349 +++1350 + 1351 ++ 1352 +++ 1353 + 1354 +++ 1355 ++ 1356 +++ 1357 +++ 1358+++ 1359 1360 +++ 1361 +++ 1362 +++ 1363 +++ 1364 +++ 1365 +++ 1366 +++1367 +++ 1368 +++ 1369 +++ 1370 +++ 1371 +++ 1372 +++ 1373 +++ 1374 +++1375 ++ 1376 +++ 1377 +++ 1378 +++ 1379 +++ 1380 +++ 1381 ++ 1382 + 1383+++ 1384 +++ 1385 +++ 1386 ++ 1387 +++ 1388 +++ 1389 +++ 1390 +++ 1391+++ 1392 +++ 1393 +++ 1394 +++ 1395 +++ 1396 +++ 1397 +++ 1398 ++ 1399+++ 1400 +++ 1401 +++ 1402 +++ 1403 +++ 1404 +++ 1405 +++ 1406 +++ 1407+++ 1408 +++ 1409 +++ 1410 +++ 1411 +++ 1412 +++ 1413 +++ 1414 +++ 1415+++ 1416 +++ 1417 ++ 1418 +++ 1419 +++ 1420 ++ 1421 +++ 1422 +++ 1423+++ 1424 +++ 1425 +++ 1426 +++ 1427 +++ 1428 +++ 1429 +++ 1430 +++ 1431+++ 1432 +++ 1433 ++ 1434 +++ 1435 +++ 1436 ++ 1437 ++ 1438 +++ 1439 ++1440 +++ 1441 ++ 1442 +++ 1443 +++ 1444 +++ 1445 +++ 1446 +++ 1447 +++1448 1449 +++ 1450 +++ 1451 +++ 1452 +++ 1453 +++ 1454 +++ 1455 +++ 1456+++ 1457 +++ 1458 +++ 1459 +++ 1460 +++ 1461 +++ 1462 +++ 1463 +++ 1464+++ 1465 +++ 1466 ++ 1467 +++ 1468 +++ 1469 ++ 1470 +++ 1471 +++ 1472+++ 1473 +++ 1474 +++ 1475 +++ 1476 +++ 1477 +++ 1478 +++ 1479 +++ 1480+++ 1481 +++ 1482 +++ 1483 +++ 1484 +++ 1485 +++ 1486 +++ 1487 +++ 1488+++ 1489 +++ 1490 +++ 1491 ++ 1492 ++ 1493 +++ 1494 +++ 1495 +++ 1496+++ 1497 +++ 1498 +++ 1499 ++ 1500 +++ 1501 +++ 1502 +++ 1503 ++ 1504+++ 1505 +++ 1506 +++ 1507 ++ 1508 +++ 1509 +++ 1510 +++ 1511 +++ 1512+++ 1513 +++ 1514 +++ 1515 +++ 1516 +++ 1517 +++ 1518 +++ 1519 +++ 1520+++ 1521 +++ 1522 +++ 1523 +++ 1524 +++ 1525 +++ 1526 +++ 1527 +++ 1528++ 1529 +++ 1530 +++ 1531 ++ 1532 +++ 1533 +++ 1534 ++ 1535 +++ 1536 ++1537 +++ 1538 + 1539 +++ 1540 + 1541 +++ 1542 +++ 1543 1544 +++ 1545 +++1546 +++ 1547 ++ 1548 +++ 1549 +++ 1550 ++ 1551 +++ 1552 +++ 1553 +++1554 +++ 1555 +++ 1556 +++ 1557 +++ 1558 ++ 1559 +++ 1560 +++ 1561 +++1562 +++ 1563 +++ 1564 ++ 1565 + 1566 +++ 1567 +++ 1568 +++ 1569 +++1570 +++ 1571 +++ 1572 +++ 1573 +++ 1574 ++ 1575 ++ 1576 +++ 1577 +++1578 +++ 1579 +++ 1580 +++ 1581 +++ 1582 +++ 1583 ++ 1584 +++ 1585 +++1586 +++ 1587 +++ 1588 +++ 1589 +++ 1590 +++ 1591 +++ 1592 +++ 1593 +++1594 +++ 1595 +++ 1596 +++ 1597 +++ 1598 +++ 1599 +++ 1600 +++ 1601 +++1602 +++ 1603 ++ 1604 +++ 1605 +++ 1606 +++ 1607 ++ 1608 +++ 1609 +++1610 +++ 1611 +++ 1612 +++ 1613 +++ 1614 +++ 1615 +++ 1616 +++ 1617 +++1618 +++ 1619 +++ 1620 +++ 1621 +++ 1622 +++ 1623 +++ 1624 +++ 1625 ++1626 +++ 1627 +++ 1628 +++ 1629 +++ 1630 +++ 1631 ++ 1632 ++ 1633 +++1634 ++ 1635 +++ 1636 ++ 1637 +++ 1638 +++ 1639 +++ 1640 +++ 1641 +++1642 +++ 1643 ++ 1644 +++ 1645 +++ 1646 +++ 1647 +++ 1648 +++ 1649 ++1650 +++ 1651 ++ 1652 +++ 1653 +++ 1654 +++ 1655 +++ 1656 +++ 1657 +++1658 ++ 1659 +++ 1660 +++ 1661 +++ 1662 ++ 1663 +++ 1664 +++ 1665 +++1666 +++ 1667 ++ 1668 +++ 1669 +++ 1670 ++ 1671 +++ 1672 +++ 1673 +++1674 +++ 1675 ++ 1676 +++ 1677 +++ 1678 + 1679 +++ 1680 +++ 1681 +++1682 +++ 1683 +++ 1684 +++ 1685 +++ 1686 +++ 1687 +++ 1688 +++ 1689 +++1690 +++ 1691 ++ 1692 ++ 1693 +++ 1694 +++ 1695 +++ 1696 +++ 1697 +++1698 +++ 1699 +++ 1700 +++ 1701 +++ 1702 +++ 1703 +++ 1704 +++ 1705 +++1706 ++ 1707 ++ 1708 +++ 1709 +++ 1710 +++ 1711 +++ 1712 +++ 1713 +++1714 ++ 1715 +++ 1716 ++ 1717 +++ 1718 +++ 1719 +++ 1720 +++ 1721 +++1722 +++ 1723 +++ 1724 +++ 1725 ++ 1726 +++ 1727 +++ 1728 +++ 1729 +++1730 +++ 1731 +++ 1732 1733 ++ 1734 +++ 1735 +++ 1736 ++ 1737 +++ 1738+++ 1739 +++ 1740 +++ 1741 +++ 1742 +++ 1743 +++ 1744 ++ 1745 +++ 1746+++ 1747 +++ 1748 +++ 1749 +++ 1750 +++ 1751 +++ 1752 ++ 1753 ++ 1754+++ 1755 ++ 1756 +++ 1757 +++ 1758 +++ 1759 +++ 1760 ++ 1761 ++ 1762 +++1763 +++ 1764 ++ 1765 +++ 1766 +++ 1767 +++ 1768 ++ 1769 ++ 1770 +++1771 +++ 1772 ++ 1773 +++ 1774 +++ 1775 +++ 1776 +++ 1777 +++ 1778 +++1779 +++ 1780 ++ 1781 +++ 1782 +++ 1783 +++ 1784 +++ 1785 +++ 1786 ++1787 ++ 1788 +++ 1789 +++ 1790 +++ 1791 +++ 1792 +++ 1793 +++ 1794 ++1795 +++ 1796 +++ 1797 +++ 1798 +++ 1799 +++ 1800 +++ 1801 +++ 1802 +++1803 +++ 1804 +++ 1805 ++ 1806 +++ 1807 +++ 1808 +++ 1809 +++ 1810 +++1811 +++ 1812 ++ 1813 +++ 1814 +++ 1815 +++ 1816 +++ 1817 +++ 1818 +++1819 ++ 1820 ++ 1821 +++ 1822 +++ 1823 +++ 1824 +++ 1825 +++ 1826 +++1827 +++ 1828 +++ 1829 +++ 1830 +++ 1831 +++ 1832 +++ 1833 +++ 1834 +++1835 +++ 1836 +++ 1837 +++ 1838 +++ 1839 +++ 1840 +++ 1841 +++ 1842 +++1843 +++ 1844 +++ 1845 +++ 1846 +++ 1847 +++ 1848 +++ 1849 ++ 1850 +++1851 +++ 1852 +++ 1853 ++ 1854 +++ 1855 +++ 1856 +++ 1857 +++ 1858 ++1859 +++ 1860 +++ 1861 +++ 1862 +++ 1863 +++ 1864 +++ 1865 ++ 1866 +++1867 +++ 1868 +++ 1869 +++ 1870 ++ 1871 +++ 1872 +++ 1873 +++ 1874 +++1875 ++ 1876 +++ 1877 ++ 1878 ++ 1879 +++ 1880 ++ 1881 +++ 1882 + 1883+++ 1884 +++ 1885 +++ 1886 ++ 1887 +++ 1888 ++ 1889 +++ 1890 ++ 1891 +++1892 +++ 1893 +++ 1894 +++ 1895 +++ 1896 +++ 1897 +++ 1898 ++ 1899 +++1900 ++ 1901 +++ 1902 +++ 1903 +++ 1904 +++ 1905 +++ 1906 +++ 1907 +++1908 +++ 1909 +++ 1910 +++ 1911 +++ 1912 +++ 1913 +++ 1914 +++ 1915 +++1916 +++ 1917 +++ 1918 +++ 1919 +++ 1920 ++ 1921 +++ 1922 +++ 1923 ++1924 +++ 1925 +++ 1926 +++ 1927 +++ 1928 ++ 1929 +++ 1930 +++ 1931 +++1932 +++ 1933 +++ 1934 +++ 1935 +++ 1936 +++ 1937 ++ 1938 +++ 1939 ++1940 +++ 1941 +++ 1942 ++ 1943 ++ 1944 +++ 1945 +++ 1946 +++ 1947 ++1948 +++ 1949 +++ 1950 +++ 1951 +++ 1952 +++ 1953 +++ 1954 +++ 1955 +++1956 +++ 1957 ++ 1958 +++ 1959 +++ 1960 +++ 1961 +++ 1962 +++ 1963 +++1964 +++ 1965 +++ 1966 +++ 1967 ++ 1968 +++ 1969 +++ 1970 +++ 1971 +++1972 +++ 1973 +++ 1974 +++ 1975 +++ 1976 +++ 1977 +++ 1978 +++ 1979 +++1980 +++ 1981 +++ 1982 ++ 1983 +++ 1984 ++ 1985 ++ 1986 +++ 1987 +++1988 +++ 1989 +++ 1990 +++ 1991 +++ 1992 +++ 1993 +++ 1994 +++ 1995 +++1996 +++ 1997 ++ 1998 +++ 1999 ++ 2000 +++ 2001 +++ 2002 +++ 2003 +++2004 +++ 2005 ++ 2006 +++ 2007 +++ 2008 ++ 2009 +++ 2010 +++ 2011 +++2012 +++ 2013 +++ 2014 +++ 2015 +++ 2016 ++ 2017 +++ 2018 +++ 2019 +++2020 +++ 2021 ++ 2022 +++ 2023 +++ 2024 ++ 2025 +++ 2026 +++ 2027 +++2028 +++ 2029 +++ 2030 +++ 2031 +++ 2032 ++ 2033 +++ 2034 +++ 2035 +++2036 +++ 2037 +++ 2038 +++ 2039 +++ 2040 +++ 2041 +++ 2042 +++ 2043 +++2044 +++ 2045 ++ 2046 +++ 2047 ++ 2048 +++ 2049 +++ 2050 +++ 2051 +++2052 +++ 2053 +++ 2054 +++ 2055 +++ 2056 ++ 2057 +++ 2058 +++ 2059 +++2060 +++ 2061 +++ 2062 +++ 2063 +++ 2064 +++ 2065 +++ 2066 +++ 2067 +++2068 +++ 2069 +++ 2070 +++ 2071 +++ 2072 ++ 2073 +++ 2074 ++ 2075 +++2076 +++ 2077 +++ 2078 ++ 2079 +++ 2080 ++ 2081 +++ 2082 ++ 2083 +++2084 +++ 2085 +++ 2086 +++ 2087 +++ 2088 ++ 2089 +++ 2090 +++ 2091 +++2092 +++ 2093 +++ 2094 +++ 2095 +++ 2096 +++ 2097 +++ 2098 +++ 2099 +++2100 +++ 2101 +++ 2102 +++ 2103 +++ 2104 +++ 2105 +++ 2106 +++ 2107 +++2108 +++ 2109 +++ 2110 + 2111 +++ 2112 ++ 2113 +++ 2114 +++ 2115 +++2116 +++ 2117 +++ 2118 +++ 2119 +++ 2120 +++ 2121 +++ 2122 +++ 2123 +++2124 +++ 2125 +++ 2126 +++ 2127 +++ 2128 ++ 2129 +++ 2130 +++ 2131 +2132 +++ 2133 +++ 2134 +++ 2135 ++ 2136 +++ 2137 +++ 2138 +++ 2139 +++2140 ++ 2141 +++ 2142 +++ 2143 +++ 2144 +++ 2145 +++ 2146 +++ 2147 +++2148 ++ 2149 +++ 2150 +++ 2151 +++ 2152 ++ 2153 +++ 2154 +++ 2155 ++2156 +++ 2157 + 2158 ++ 2159 +++ 2160 ++ 2161 +++ 2162 +++ 2163 +++ 2164+++ 2165 +++ 2166 ++ 2167 +++ 2168 +++ 2169 +++ 2170 +++ 2171 +++ 2172+++ 2173 +++ 2174 ++ 2175 ++ 2176 +++ 2177 +++ 2178 +++ 2179 +++ 2180+++ 2181 +++ 2182 +++ 2183 +++ 2184 +++ 2185 ++ 2186 +++ 2187 +++ 2188+++ 2189 +++ 2190 +++ 2191 +++ 2192 +++ 2193 +++ 2194 +++ 2195 +++ 2196+++ 2197 +++ 2198 +++ 2199 ++ 2200 ++ 2201 +++ 2202 +++ 2203 +++ 2204+++ 2205 +++ 2206 +++ 2207 +++ 2208 +++ 2209 +++ 2210 +++ 2211 +++ 2212++ 2213 +++ 2214 +++ 2215 ++ 2216 +++ 2217 +++ 2218 +++ 2219 ++ 2220 ++2221 ++ 2222 ++ 2223 +++ 2224 +++ 2225 ++ 2226 ++ 2227 +++ 2228 +++ 2229++ 2230 +++ 2231 +++ 2232 ++ 2233 +++ 2234 +++ 2235 +++ 2236 +++ 2237+++ 2238 +++ 2239 +++ 2240 ++ 2241 +++ 2242 +++ 2243 +++ 2244 +++ 2245+++ 2246 +++ 2247 ++ 2248 +++ 2249 +++ 2250 +++ 2251 +++ 2252 +++ 2253++ 2254 ++ 2255 +++ 2256 +++ 2257 +++ 2258 +++ 2259 +++ 2260 +++ 2261+++ 2262 +++ 2263 +++ 2264 +++ 2265 +++ 2266 +++ 2267 +++ 2268 +++ 2269+++ 2270 +++ 2271 +++ 2272 +++ 2273 +++ 2274 ++ 2275 ++ 2276 +++ 2277+++ 2278 +++ 2279 +++ 2280 +++ 2281 ++ 2282 +++ 2283 +++ 2284 +++ 2285+++ 2286 +++ 2287 +++ 2288 +++ 2289 +++ 2290 ++ 2291 +++ 2292 +++ 2293+++ 2294 ++ 2295 ++ 2296 +++ 2297 +++ 2298 +++ 2299 +++ 2300 ++ 2301 +++2302 +++ 2303 ++ 2304 +++ 2305 +++ 2306 +++ 2307 +++ 2308 +++ 2309 +++2310 +++ 2311 +++ 2312 +++ 2313 +++ 2314 ++ 2315 +++ 2316 +++ 2317 +++2318 +++ 2319 ++ 2320 +++ 2321 ++ 2322 +++ 2323 ++ 2324 ++ 2325 +++ 2326+++ 2327 ++ 2328 ++ 2329 +++ 2330 +++ 2331 +++ 2332 +++ 2333 ++ 2334 +++2335 ++ 2336 +++ 2337 +++ 2338 +++ 2339 +++ 2340 +++ 2341 +++ 2342 +++2343 +++ 2344 +++ 2345 +++ 2346 +++ 2347 +++ 2348 +++ 2349 ++ 2350 ++2351 +++ 2352 +++ 2353 +++ 2354 ++ 2355 +++ 2356 +++ 2357 +++ 2358 +++2359 ++ 2360 ++ 2361 +++ 2362 +++ 2363 ++ 2364 +++ 2365 +++ 2366 +++2367 +++ 2368 +++ 2369 +++ 2370 +++ 2371 +++ 2372 +++ 2373 +++ 2374 +++2375 ++ 2376 +++ 2377 +++ 2378 +++ 2379 +++ 2380 +++ 2381 +++ 2382 +++2383 ++ 2384 +++ 2385 +++ 2386 +++ 2387 ++ 2388 +++ 2389 ++ 2390 +++2391 +++ 2392 +++ 2393 ++ 2394 +++ 2395 +++ 2396 ++ 2397 +++ 2398 +++2399 +++ 2400 ++ 2401 +++ 2402 +++ 2403 +++ 2404 +++ 2405 +++ 2406 +++2407 ++ 2408 +++ 2409 +++ 2410 +++ 2411 +++ 2412 +++ 2413 +++ 2414 ++2415 +++ 2416 +++ 2417 +++ 2418 +++ 2419 ++ 2420 ++ 2421 +++ 2422 ++2423 +++ 2424 +++ 2425 +++ 2426 +++ 2427 +++ 2428 +++ 2429 +++ 2430 ++2431 +++ 2432 +++ 2433 ++ 2434 +++ 2435 +++ 2436 +++ 2437 +++ 2438 +++2439 +++ 2440 +++ 2441 ++ 2442 ++ 2443 +++ 2444 ++ 2445 +++ 2446 +++2447 +++ 2448 +++ 2449 +++ 2450 +++ 2451 +++ 2452 +++ 2453 +++ 2454 ++2455 +++ 2456 +++ 2457 +++ 2458 +++ 2459 +++ 2460 +++ 2461 +++ 2462 +++2463 +++ 2464 ++ 2465 +++ 2466 +++ 2467 +++ 2468 +++ 2469 ++ 2470 +++2471 ++ 2472 ++ 2473 +++ 2474 +++ 2475 +++ 2476 +++ 2477 +++ 2478 +++2479 +++ 2480 ++ 2481 +++ 2482 +++ 2483 +++ 2484 +++ 2485 +++ 2486 +++2487 +++ 2488 +++ 2489 ++ 2490 +++ 2491 +++ 2492 +++ 2493 +++ 2494 +++2495 +++ 2496 +++ 2497 +++ 2498 +++ 2499 +++ 2500 +++ 2501 ++ 2502 +++2503 +++ 2504 ++ 2505 +++ 2506 ++ 2507 +++ 2508 +++ 2509 +++ 2510 +++2511 +++ 2512 +++ 2513 ++ 2514 +++ 2515 +++ 2516 ++ 2517 +++ 2518 +++2519 +++ 2520 ++ 2521 +++ 2522 +++ 2523 ++ 2524 +++ 2525 ++ 2526 +++2527 +++ 2528 +++ 2529 +++ 2530 +++ 2531 +++ 2532 +++ 2533 +++ 2534 +++2535 ++ 2536 +++ 2537 ++ 2538 +++ 2539 +++ 2540 +++ 2541 +++ 2542 +++2543 +++ 2544 + 2545 +++ 2546 +++ 2547 +++ 2548 +++ 2549 +++ 2550 ++2551 +++ 2552 +++ 2553 +++ 2554 +++ 2555 +++ 2556 ++ 2557 +++ 2558 +++2559 +++ 2560 +++ 2561 +++ 2562 +++ 2563 +++ 2564 +++ 2565 ++ 2566 +++2567 +++ 2568 ++ 2569 +++ 2570 ++ 2571 +++ 2572 +++ 2573 +++ 2574 ++2575 +++ 2576 +++ 2577 +++ 2578 +++ 2579 +++ 2580 +++ 2581 +++ 2582 +++2583 ++ 2584 ++ 2585 +++ 2586 ++ 2587 ++ 2588 +++ 2589 +++ 2590 +++ 2591+++ 2592 +++ 2593 +++ 2594 +++ 2595 +++ 2596 +++ 2597 ++ 2598 +++ 2599++ 2600 +++ 2601 ++ 2602 ++ 2603 +++ 2604 +++ 2605 ++ 2606 +++ 2607 +++2608 +++ 2609 +++ 2610 +++ 2611 +++ 2612 ++ 2613 +++ 2614 ++ 2615 ++2616 +++ 2617 ++ 2618 +++ 2619 +++ 2620 ++ 2621 ++ 2622 +++ 2623 ++ 2624++ 2625 +++ 2626 +++ 2627 +++ 2628 +++ 2629 +++ 2630 +++ 2631 +++ 2632+++ 2633 ++ 2634 +++ 2635 +++ 2636 + 2637 +++ 2638 +++ 2639 +++ 2640 +++2641 +++ 2642 +++ 2643 +++ 2644 +++ 2645 +++ 2646 +++ 2647 +++ 2648 +++2649 +++ 2650 ++ 2651 +++ 2652 +++ 2653 +++ 2654 +++ 2655 +++ 2656 +++2657 ++ 2658 ++ 2659 ++ 2660 +++ 2661 +++ 2662 ++ 2663 +++ 2664 +++ 2665+++ 2666 ++ 2667 +++ 2668 ++ 2669 +++ 2670 +++ 2671 +++ 2672 +++ 2673+++ 2674 +++ 2675 +++ 2676 +++ 2677 +++ 2678 ++ 2679 ++ 2680 ++ 2681 +++2682 +++ 2683 +++ 2684 +++ 2685 +++ 2686 +++ 2687 ++ 2688 +++ 2689 ++2690 +++ 2691 +++ 2692 ++ 2693 ++ 2694 +++ 2695 +++ 2696 +++ 2697 +++2698 +++ 2699 +++ 2700 +++ 2701 +++ 2702 +++ 2703 +++ 2704 +++ 2705 +++2706 +++ 2707 +++ 2708 +++ 2709 +++ 2710 ++ 2711 ++ 2712 +++ 2713 +++2714 +++ 2715 +++ 2716 +++ 2717 +++ 2718 +++ 2719 +++ 2720 +++ 2721 +++2722 +++ 2723 +++ 2724 +++ 2725 +++ 2726 +++ 2727 +++ 2728 +++ 2729 +++2730 ++ 2731 ++ 2732 ++ 2733 ++ 2734 ++ 2735 ++ 2736 ++ 2737 +++ 2738+++ 2739 +++ 2740 +++ 2741 ++ 2742 ++ 2743 +++ 2744 +++ 2745 +++ 2746+++ 2747 +++

Other Embodiments

All publications and patents referred to in this disclosure areincorporated herein by reference to the same extent as if eachindividual publication or patent application were specifically andindividually indicated to be incorporated by reference. Should themeaning of the terms in any of the patents or publications incorporatedby reference conflict with the meaning of the terms used in thisdisclosure, the meaning of the terms in this disclosure are intended tobe controlling. Furthermore, the foregoing discussion discloses anddescribes merely exemplary embodiments of the invention. One skilled inthe art will readily recognize from such discussion and from theaccompanying drawings and claims, that various changes, modificationsand variations can be made therein without departing from the spirit andscope of the invention as defined in the following claims.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20180185364A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1-185. (canceled)
 186. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: Ring A is pyridine; Ring B is pyridine; Ring C ispyrrolidine; W is O; X is O; (Y)_(o) is a bond; Z is NH: R₁ is halo, CN,F₅S, SiR₃, OH, NRR, C₁-C₆ alkyl or fluoroalkyl, C₁-C₆ alkoxy orfluoroalkoxy, C₁-C₆ alkenyl, C₁-C₆ alkynyl, (C₁-C₉ alkylene)-R₄ whereinup to four CH₂ units are independently replaced with O, CO, S, SO, SO₂or NR, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl or heterocyclic ring whereinanywhere from 1 to 4 ring atoms are independently O, S, N, or NR, orC₃-C₁₀ cycloalkyl; R₂ is halo, OH, NRR, azide, CN, CO₂R, C₁-C₆ alkyl orfluoroalkyl, C₁-C₆ alkoxy or fluoroalkoxy, C₁-C₆ alkenyl, C₁-C₆ alkynyl,C₆-C₁₀ aryl, C₃-C₁₃ heteroaryl or heterocyclic ring wherein anywherefrom 1 to 4 ring atoms are independently O, S, N, or NR, C₃-C₁₀cycloalkyl, or a (C₁-C₉ alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR; or two R₂ groupstaken together may form a ═CH₂ or ═O group; R₃ is halo, CN, OH, CO₂R,C₁-C₆ alkyl or fluoroalkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxyor fluoroalkoxy, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl or heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR, C₃-C₁₀ cycloalkyl, or a (C₁-C₉ alkylene)-R₄ wherein up to four CH₂units are independently replaced with O, CO, S, SO, SO₂ or NR; or two R₃groups taken together may form a ═CH₂ or ═O group; R₄ is H, azide, CF₃,CHF₂, OR, CCH, CO₂R, OH, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl orheterocycloalkyl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR, C₃-C₁₀ cycloalkyl, NRR, NRCOR, CONRR, CN,halo, or SO₂R; R is independently H, OH, CO₂H, CO₂, C₁-C₆ alkyl, C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl orheterocycloalkyl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR, or C₃-C₁₀ cycloalkyl; n is 0, 1, 2, or 3;p is 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, or 5; and

is independently a single bond or a double bond; provided that themoieties containing ring B and ring C are substituted at adjacentpositions on ring A.
 187. The compound of claim 186, wherein Ri is halo,CN, C₁-C₆ aliphatic, C₁-C₆ alkoxy, C₃-C₈ cycloalkyl, phenyl, pyridyl,pyrimidine, indole, aza-indole, azetidine, or thiophene ring, whereinall rings may be substituted with halo, C₁-C₆ aliphatic, C₁-C₆ alkoxy,C₁-C₆ fluoroaliphatic, C₁-C₆ fluoroalkoxy, OH, CH₂OH, CH₂OCH₃, CN, CO₂H,amino, amido, C₃-C₁₀ heteroaryl, C₃-C₁₀ heterocycloalkyl, or a (C₁-C₈aliphatic)-R₄ wherein up to three CH₂ units may be replaced with O, CO,S, SO, SO₂ or NR.
 188. The compound of claim 186, wherein Ri is selectedfrom CH₃, Cl, F, CN, OCH₃, CF₃, CH₂, CH₃, tBu, CH(CH₃)₂,


189. The compound of claim 186, wherein R2 is halo, OH, CN, azide,amino, C₁-C₆ aliphatic or fluoroaliphatic, C1-C₆ alkoxy or fluoroalkoxy,C₃-C₁₀ mono- or bicyclic heterocyclic ring wherein up to 4 carbon atomsmay be replaced with O, S, N, or NR, or a (C₁-C₈ aliphatic)-R₄ whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR.190. The compound of claim 186, wherein R₂ is Cl, F, OH, CN, N₃, NH₂,NH(CH₃), N(CH₃)₂, CH₃, CH₂OH, CH₂CH₃, CH(CH₃)₂, CHF₂, OCH₃, OCF₃, OCHF₂,OCH(CH₃)₂, C(O)CH₃, CH₂CH₂OH, CH₂NH₂, NH(CH₂)₂OH, NH(CH₂)₂N(CH₃)₂,NH(CH₂)₂NH₂, NH(CH₂)₃NH₂, NH(CH₂)₂OCH₃, NHCH(CH₃)₂,

or CO2H,
 191. The compound of claim 186, wherein R₃ is halo, CN, C₁-C₆aliphatic or fluoroaliphatic, C₁-C₆ alkoxy, or C₃-C₁₀ mono- or bicyclicheteroaryl or heterocycloalkyl wherein up to 4 carbon atoms may bereplaced by O, S, N, or NR.
 192. The compound of claim 186, wherein R₃is Cl, F, CN, CH₃, OCH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃, OCH₂CH₃,CH₂OCH₃, CH(CH₃)₂, CCH, CO₂CH₃, tBu, ═CH₂, ═O,


193. The compound of claim 186, wherein n is 1,
 194. The compound ofclaim 186, wherein n is
 2. 195. The compound of claim 186, wherein p is0,
 196. The compound of claim 186, wherein p is
 1. 197. The compound ofclaim 186, wherein p is 2,
 198. A pharmaceutical composition comprisinga compound of formula

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: Ring A is pyridine; Ring B is pyridine; Ring C ispyrrolidine; W is O; X is O; (Y)_(o) is a bond; Z is NH; R₁ is halo, CN,F₅S, SiR₃, OH, NRR, C₁-C₆ alkyl or fluoroalkyl, C₁-C₆ alkoxy orfluoroalkoxy, C₁-C₆ alkenyl, C₁-C₆ alkynyl, (C₁-C₉ alkylene)-R₄ whereinup to four CH₂ units are independently replaced with O, CO, S, SO, SO₂or NR, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl or heterocyclic ring whereinanywhere from 1 to 4 ring atoms are independently O, S, N, or NR, orC₃-C₁₀ cycloalkyl; R₂ is halo, OH, NRR, azide, ON, CO₂R, C₁-C₆ alkyl orfluoroalkyl, C₁-C₆ alkoxy or fluoroalkoxy, C₁-C₆ alkenyl, C₁-C₆ alkynyl,C₅-C₁₀ aryl, C₃-C₁₃ heteroaryl or heterocyclic ring wherein anywherefrom 1 to 4 ring atoms are independently O, S, N, or NR, C₃-C₁₀cycloalkyl, or a (C₁-C₉ alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, S, SO, SO₂ or NR; or two R₂ groupstaken together may form a ═CH₂ or ═O group; R₃ is halo, CN, OH, CO₂R,C1-C₆ alkyl or fluoroalkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C1-C₆ alkoxyor fluoroalkoxy, or C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl or heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR, C₃-C₁₀ cycloalkyl, or a (C₁-C₉ alkylene)-R₄ wherein up to four CH₂units are independently replaced with O, CO, S, SO, SO₂ or NR; or two R₃groups taken together may form a ═CH₂ or ═O group; R₄ is H, azide, CF₃,CHF₂, OR, CCH, CO₂R, OH, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl orheterocycloalkyl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR, C₃-C₁₀ cycloalkyl, NRR, NRCOR, CONRR, CN,halo, or SO₂R; R is independently H, OH, CO₂H, CO₂C₁-C₆ alkyl, C₁-C₆alkyl, C1-C₆ alkenyl, C₁-C₆ alkynyl, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl orheterocycloalkyl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR, or C₃-C₁₀ cycloalkyl; n is 0, 1, 2, or 3;p is 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, or 5: and

is independently a single bond or a double bond; provided that themoieties containing ring B and ring C are substituted at adjacentpositions on ring A; and a pharmaceutically acceptable carrier,
 199. Thepharmaceutical composition of claim 198, further comprising one or moreadditional therapeutic agent(s).
 200. The pharmaceutical composition ofclaim 199, wherein the additional therapeutic agent is a mucolyticagent, bronchodilator, an antibiotic, an anti-infective agent, a CFTRmodulator, or an anti-inflammatory agent.
 201. The pharmaceuticalcomposition of claim 199, wherein the additional therapeutic agent is aCFTR modulator.
 202. The pharmaceutical composition of claim 199,wherein the additional therapeutic agent is a CFTR corrector.
 203. Thepharmaceutical composition of claim 199, wherein the additionaltherapeutic agent is

or a pharmaceutically acceptable salt thereof.
 204. The pharmaceuticalcomposition of claim 199, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof,
 205. The pharmaceuticalcomposition of claim 199, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.
 206. The pharmaceuticalcomposition of claim 199, wherein the additional therapeutic agent is aCFTR potentiator.
 207. The pharmaceutical composition of claim 199,wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.
 208. The pharmaceuticalcomposition of claim 199, wherein the additional therapeutic agents area CFTR corrector and a CFTR potentiator.
 209. The pharmaceuticalcomposition of claim 199, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.
 210. The pharmaceuticalcomposition of claim 199, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.
 211. The pharmaceuticalcomposition of claim 199, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.
 212. A kit comprising acompound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence Ring A is pyridine; Ring B is pyridine; Ring C ispyrrolidine; W is O; X is O; (Y)O is a bond; Z is NH; R₁ is halo, CN,FSS, SiR3, OH, NRR, C₁-C₆ alkyl or fluoroalkyl, C₁-C₆ alkoxy orfluoroalkoxy, C₁-C₆ alkenyl, C₁-C₆ alkynyl, (C₁-C₉ alkylene)-R₄ whereinup to four CH₂ units are independently replaced with O, CO, S, SO, SO₂or NR, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl or heterocyclic ring whereinanywhere from 1 to 4 ring atoms are independently O, S, N, or NR, orC₃-C₁₀ cycloalkyl; R₂ is halo, OH, NRR, azide, ON, CO₂R, C₁-C₆ alkyl orfluoroalkyl, C₁-C₆ alkoxy or fluoroalkoxy, C₁-C₆ alkenyl, C₁-C₆ alkynyl,C₆-C₁₀ aryl, C₃-C₁₃ heteroaryl or heterocyclic ring wherein anywherefrom 1 to 4 ring atoms are independently O, S, N, or NR, C₃-C₁₀cycloalkyl, or a (C₁-C₉ alkylene)-R₄ wherein up to four CH₂ units areindependently replaced with O, CO, 5, SO, SO₂ or NR; or two R₂ groupstaken together may form a ═CH₂ or ═O group; R₃ is halo, CN, OH, CO₂R,C₁-C₆ alkyl or fluoroalkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxyor fluoroalkoxy, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl or heterocyclic ringwherein anywhere from 1 to 4 ring atoms are independently O, S, N, orNR, C₃-C₁₀ cycloalkyl, or a (C₁-C₉ alkylene)-R₄ wherein up to four CH₂units are independently replaced with O, CO, S, SO, SO₂ or NR; or two R₃groups taken together may form a ═CH₂ or ═O group; R₄ is H, azide, CF₃,CHF₂, OR, CCH, CO₂R, OH, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl orheterocycloalkyl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR, C₃-C₁₀ cycloalkyl, NRR, NRCOR, CONRR, ON,halo, or SO₂R; R is independently H, OH, CO₂H, OC₂, C₁-C₆ alkyl, C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₆-C₁₀ aryl, C₃-C₁₀ heteroaryl orheterocycloalkyl wherein anywhere from 1 to 4 ring atoms areindependently O, S, N, or NR, or C₃-C₁₀ cycloalkyl; n is 0, 1, 2, or 3;p is 0, 1, 2, or 3; q is 0, 1,2, 3, 4, or 5; and

is independently a single bond or a double bond; provided that themoieties containing ring B and ring C are substituted at adjacentpositions on ring A; and one or more additional therapeutic agent(s).213. The compound of claim 186, or a pharmaceutically acceptable saltthereof, wherein the compound is:N-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-Amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide,N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-ylipyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(1,3-dimethylbutoxy)-4-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidemethyl(2S)-1-[3-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyridylipyrrolidine-2-carboxylateN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isobutoxy-2-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(p-tolyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-ylipyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(5-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropoxy-4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(6-isopropoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isobutyl(methyl)amino]-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(8-oxa-4-azaspiro[4.4]nonan-4-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(cyclobutoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isobutoxy-2-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isopropylamino)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,3R)-2,3-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-phenylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-[(1-methylcyclopropyl)methoxy]-3-pyridyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxyphenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(p-tolyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,2,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methoxy-2-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridybsulfonyl]-2-[(2R5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-5-methyl-pyridine-3-carboxamide6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[[6-(1-piperidyl)-2-pyridyl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)-5-methyl-pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isopropoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-4-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-propoxy-4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[2-(1,1-dimethylpropyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[5-(cyclopentoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,5-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(6-isopropoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-methyl-4-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(isobutylamino)-4-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl]sulfonyl]-6-(2-methoxy-3-pyridyl)-2-(2.2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxy-2-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-[3-(cyclopropylmethoxy)-5-fluoro-phenyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isobutoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-ethoxy-5-fluoro-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3S)-2,23-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isobutoxyphenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isobutylamino)-3-pyridyl]-2-(2.2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-[3-(2,2-dimethylpropoxy)-5-fluoro-phenyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyli-6-[6-[(1R)-2-benzyloxy-1-methyl-ethoxy]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(1-ethylpropoxy)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isopropylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyrroidin-1-yl-pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopropylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethyl-3-phenyl-pyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(3-tert-butylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2,4-dimethylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-2-methyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-methyl-3-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isobutylpyrazol-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-pyridyl)-2-(2,2,4-trimethylpyrroridin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-propoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-2,2,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2-methyl-pyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2-(2-pyridyl)pyrrolidin-1-yl]pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-phenyl-pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3S)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isopentyloxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,4-dimethylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-cyclohexyl-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,5-dimethyl-3-phenyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(1,2-dimethylpropoxy)-2-pyridyl]-2-(2,2-dimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,3-dimethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(2-fluoro-5-isobutoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamidemethyl2-[[5-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-2-pyridyl]-2-pyridyl]oxy]propanoateN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-isopropylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-methoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide6-(4-chlorophenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(o-tolyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluorophenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,3S)-2,3-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)pyrazin-2-yl]-2-(2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethyl-3-(trifluoromethyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-methoxy-2-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isopropoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(cyclopropylmethoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-phenyl-pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(2-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-2-methyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluoro-2-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isobutyl(methyl)amino)-2-methyl-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-methoxyphenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropoxypyrimidin-5-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(8-azaspiro[3.4]octan-8-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(1,3-dimethylbutoxy)-2-pyridyl]-2-(2,2-dimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopentyloxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-4-methyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-phenylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropylphenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[2-[isobutyl(methyl)amino]-4-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(4-chloro-3-isobutoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrroidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-4-methyl-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)pyridine-3-carboxamide6-[3-(cyclobutylmethoxy)-5-fluoro-phenyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,3,5-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(9-azaspiro[4.4]nonan-9-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-cyclopropylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyn-2-(3-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl}-6-[6-(isopropylamino)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-isobutoxyphenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(5-isopropoxypyrazin-2-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isopropoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(8-azaspiro[3,4]octan-8-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxypyrazin-2-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3R)-2,2,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-benzylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-(2-hydroxy-1-methyl-ethoxy)-3-pyridyl)pyridine-3-carboxamide6-(4-chloro-3-isopropoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpyrrolidin-1-yl)-6-(6-isobutoxy-2-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-fluorophenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,2,5-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(3R)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isobutylamino)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(6-azaspiro[2.4]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-(2-pyridylsulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2,3,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isopropylpyrazol-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(1-ethylpropoxy)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(p-tolyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3S)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-phenoxypyrrolidin-1-yl)pyridine-3-carboxamide2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(3-ethoxy-5-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S)-2-tert-butylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-fluoro-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-(22,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(3-phenylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,23-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isopropoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(cyclopropoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopentyloxy-2-pyridy)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-methoxy-2-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2,3,3-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,3,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-4-methyl-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(5R)-2,2,5-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R)-2-tert-butylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-3-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-3-oxo-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isobutoxy-4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-5-isobutoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-chloro-3-isobutoxy-phenyl)-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(3-tert-butylpyrrolidin-1-yl)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-methoxyphenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethylpyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-5-methyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(5-isobutoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(5S)-2,2,5-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropylpyrazol-3-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxypyrazin-2-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-methoxy-pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-methoxy-2,5-dimethyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-phenylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropyl-4-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2-methylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methoxy-2-methyl-phenyl)-5-methyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-oxo-1H-pyridin-2-yl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methyl-3-phenyl-pyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(3R)-3-methylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-(2,3,3-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-2-pyridyl]-2-(2,2-dimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(7-azaspiro[a4]heptan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-phenyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(4-isopropylphenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-[(2-methoxy-3-pyridyl)sulfamoyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2R,4S)-4-fluoro-2-methyl-pyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-5-methyl-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-phenyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6,6-dimethyl-2,3-dihydropyran-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butyl5-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylateN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-5-vinyl-pyridine-3-carboxamideN-[(6-amino-5-hydroxy-2-pyridyl)sulfonyl]-24(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-hex-1-enyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-norbornan-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[(E)-2-cyclopropylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[4-(trifluoromethyl)cyclohexen-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]cyclohex-3-ene-1-carboxylicacidN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-3-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-phenyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidetert-butyl3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylateN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-[6-(1-ethylpropylamino)-3-pyridyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-(isobutylamino)-3-pyridyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[[(1S)-1,2-dimethylpropyl]amino]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(3S)-2.2-dideuterio-3,5,5-trimethyl-pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamidebenzyl4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyn-3,6-dihydro-2H-pyridine-1-carboxylateN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(5,5-dimethyl-3-oxo-cyclohexen-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxy-5-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isobutylamino)-3-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-cyano-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-methyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-isopropenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2.5-dimethylpyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-hydroxy-pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(5-isobutylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyrrolyl)sulfonyl]-6-(3,4-dihydro-2H-pyran-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxy-5,5-dimethyl-cyclohexyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1-methylpyrazol-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[[(1R)-1,2-dimethylpropyl]amino]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-pyridylsulfamoyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-dihydrofuran-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1,4-dioxaspiro[4.5]dec-8-en-8-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide5-(4-acetylcyclonexen-1-yl)-N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3,3-dimethyl-6-oxo-cyclonexen-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[[(1S)-1,3-dimethylbutyl]amino]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1,4-dioxaspiro[4.5]dec-8-en-9-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-4-methyl-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-methoxy-4-methyl-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-[(6-methoxy-2-pyridyl)sulfonyl]-2-[(4S)-2,2.4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclohexylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(3,4-dihydro-2H-pyran-6-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(3,4-dihydro-2H-pyran-5-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2-dimethylpropyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideEthyl(E)-3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-3-pyridyl]prop-2-enoateN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-isopropyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-[6-[isobutyl(methyl)amino]-3-pyridyl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl}-6-ethyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2-dimethylprop-1-enyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-((6-aminopyridin-2-yl)sulfonyl)-6-(tert-butyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-4-methyl-3-pyridyl)pyridine-3-carboxamidetert-butyl4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylateN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxypyrazin-2-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-dihydro-2H-pyran-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[[(1R)-1,3-dimethylbutyl]amino]-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxy-4-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydrofuran-3-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-(4-methoxyphenyl)vinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-methoxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isobutoxy-2-methyl-3-pyridyl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-2-[(4S)-3,3-dideuteno-2,2-dimethyl-4-(trideutenomethyl)pyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4,7,7-trimethyl-3-bicyclo[2.2.1]hept-2-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(E)-3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-3-pyridyl]prop-2-enoicacidN-[(6-amino-2-pyridyl)sulfonyl]-5-(trifluoromethyl)-2-[(4S)-2,2,4-trimethylpyroidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(trifluoromethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-methylprop-1-eny)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-5-hydroxy-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-cyano-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-(3-hydroxy-2-methyl-propoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-ethoxy-5-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-2-cyclopropylvinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-isopropoxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[(1S,2S)-2-(methoxymethyl)cyclopropyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-bicyclo[2.2.1]hept-2-enyl)-6-tert-butyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(4,7,7-trimethyl-3-bicyclo[2.2.1]hept-2-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(1,2-dimethylprop-1-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3,6-dihydro-2H-pyran-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydropyran-4-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-isobutyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(cyclohexen-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-5-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(4R)-4-ethyl-2,2-dimethyl-pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-4-ethyl-2,2-dimethyl-pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-3,3-dimethylbut-1-enyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-pent-1-enyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isobutoxy-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyn-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-(6-isopropoxy-2-methyl-3-pyridyl)pyridine-3-carboxamidetert-butyl4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylateN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-ethoxyvinyl]-2-[(4S)-2,2,4,-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-cyclopropyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-bromo-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tetrahydropyran-3-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclopentylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(1-acetyl-4-piperidyl)-N-[(6-amino-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)-6-(trifluoromethyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-chloro-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-3-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2,2,6,6-tetramethyl-3H-pyran-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-acetamido-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-3-methyl-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide,N-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2,2-dimethylpropoxy)-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexen-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-2-cyclopropylvinyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isopropoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-2,6-bis[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-isopropoxy-5-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-cyclopropylethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(difluoromethoxy)-3-pyridyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[(E)-5-methylhex-1-enyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methylprop-1-enyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butyl4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]-2,3-dihydropyrrole-1-carboxylateN-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(2-isopropoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethoxy]-4-methyl-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-aminopyridin-2-yl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-aminopyridin-2-yl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-dihydro-2H-pyran-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-ethoxyethoxy)-4-methyl-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(o-tolyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-isopropoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-isopropoxyethoxy)-4-methyl-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[2-(4-fluorophenyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(hydroxymethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(hydroxymethy)-4-methoxy-phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-phenylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isopropoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[4-(trifluoromethyl)cyclonexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[methyl(propyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-hydroxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethoxy]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(4-methoxyphenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-tert-butoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(3-methoxy-5-methyl-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-cyanophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3,5-dichlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-isopropylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-((6-aminopyridin-2-yl)sulfonyl)-5-(3,5-dichlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-2-(4-methoxyphenyl)vinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-ethoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[5-methyl-6-[(1S)-1-methylpropoxy]-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-2,4-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1-cyclohexylethoxy)-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-2-[(2S,5R)-2,5-dimethylpyrrolidin-1-yl]-6-(3-isobutoxypyrazol-1-yl)pyridine-3-carboxamideN-[[6-(4-cyclopentylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(pyrrolidin-3-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(2-methoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-((6-aminopyridin-2-yl)sulfonyl)-6-(3-fluoro-5-isobutoxyphenyl)-2-(7-methyl-5-azaspiro[3.4]octan-5-yl)nicotinamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(hydroxymethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(diethylamino)-6-methyl-4-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isobutoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2-ethoxyethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-isobutoxy-4-methyl-pyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-acetyl-2-methoxy-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(6-ethoxy-4-methyl-2-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl]sulfonyl]-2-(5,5-dimethyl-6-azaspiro[2.4]heptan-6-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-methoxy-6-methyl-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(3,5-dimethyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(1-naphthyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2,5-dimethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-prop-2-ynoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(5-methyl-7-azaspiro[2.4]heptan-7-yl)pyridine-3-carboxamideN-[[6-(3-phenyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(4-tert-butylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[4-(dimethylamino)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxy-4-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(1,1,4,4,7-pentamethyltetralin-6-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(4-isobutoxypyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(3,4-dimethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(tetrahydrofuran-2-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-tert-butyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(o-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(cyclonexylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2,5-difluorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butyl4-(6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]piperazine-1-carboxylate6-(4-isopropoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(1,3-benzothiazol-6-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(5-phenylisoxazol-3-yl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(3-chloro-4-methoxy-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-fluoro-3-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(3-ethynylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethoxy]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2,3-dimethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-[2-(2-isopropoxyethoxy)ethoxy]ethoxy]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethyl-4-(trifluoromethyl)pyrrolidin-1-yl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-methoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(5,5-dimethyl-2-oxo-cyclohexyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[3-(cyclopropylmethyl)-2,2-dimethyl-pyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2,4,5-trifluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2-fluorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[4-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-cyclohexylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3,5-difluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-ethoxy-2-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-naphthyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isopropoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[3-(methoxymethyl)-1-piperidyl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(2,4-dichlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(4-fluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxy-4-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-isopropylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1,2-dimethylpropoxy)-5-fluoro-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(4-methyl-1-naphthyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[2-[2-(2-ethoxyethoxy)ethoxy]-6-methyl-4-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(4-fluorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(1,3-benzodioxol-5-ylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[3-isopropoxy-5-(trifluoromethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[]6-[4-(2-pyridyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-2,4-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-hydroxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(1H-indol-5-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-cyanophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(8-quinolylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[benzyl(methyl)amino]-2-pyridylsulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-ethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(m-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(5-fluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-chloro-4-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-(2-pyridylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(cyclopentoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(2,3,5-trifluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-isoindolin-2-yl-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-chloroanilino)-2-pyridy]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(1R)-1-phenylethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-ethoxy-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isopropoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(diethylamino)-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclohexyl-1,2-dihydroxyethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-2-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-ethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-cyanophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-4-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2,2-dimethyl-pyrrolidin-1-yl)-6-tert-butyl-pyridine-3-carboxamide6-(2,6-dimethoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-ethoxy-4-methyl-pyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1-naphthyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-fluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-ethoxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(6-methoxy-2-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(4-ethyl-2-pyridyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(thiazol-2-ylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methoxy-2-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-ethoxy-4-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[ethyl(2-methoxyethyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-chloroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3,4-dihydro-2H-pyran-2-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(7-quinolyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(1-acetylindolin-5-yl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3,5-dimethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[3-(N-methylanilino)propylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-methoxy-3-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(E)-but-2-enoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isobutylsulfonyl-3,6-dihydro-2H-pyridin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1,2-dihydroxy-3,3-dimethylbutyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-methylcyclopentoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(6-methoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[2,3,3,3-tetradeuterio-2-(trideutenomethyl)propoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-bicyclo[2.2.1]hept-2-enyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isopropoxy-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-(1-tetrahydropyran-4-ylethoxy)-2-[(4S)-2.2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(p-tolylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isopentyloxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-isobutoxypyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(2-methylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2-chloro-4-fluoro-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-isopropylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4,5-difluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(1-phenylethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2,3-dichloroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-5-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-([6-(cyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(indan-5-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1,2-dimethylpropyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2,5-difluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3,4-difluoro-5-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-hex-1-enyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(1-phenylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[3-(cyclopentoxy)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(1-cyclohexylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-methoxycyclohexen-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-hydroxy-3,5-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-ethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-tert-butylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-methoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(2,4-dichlorophenyl)methoxy}-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-fluoro-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-ethoxy-4,5-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(azepan-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-isoquinolylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[3-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(1-methylcyclopentoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[4-(1,3-dioxolan-2-ylmethyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(benzylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(tetrahydropyran-2-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(3-methoxyphenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-chloro-5-fluoro-anilino)-2-pyridyl]sulfonyl]-2-(22,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(1-piperidylsulfonyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[3-(2-methoxyethoxymethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-ethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-fluoro-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(2-ethoxyethoxy)-6-methyl-4-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-acetylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[3-(trifluoromethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,5-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[[3-(trifluoromethyl)phenyl]methoxy]-2-pyridyl]sulfonyl}-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2,5-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-tetralin-5-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(5-chloro-3-pyridyl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-phenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(2-methoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[2-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-chloro-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(2-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1-cyclopentylethoxy)-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(2,4-dichlorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-isobutoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-sec-butoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[64(4-tert-butylcyclohexyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(3-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-isopropoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-((6-aminopyridin-2-yl)sulfonyl)-6-(tert-butyl)-2-(3-cyclopropyl-2,2-dimethylpyrrolidin-1-yl)nicotinamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-acetamido-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[4-(trifluoromethoxy)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[methyl(phenethyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(2-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(2,4,5-trifluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(1H-indol-5-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(2-chlorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-triethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(3-chlorobenzoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(4-pentylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(1,3-dihydrobenzo[de]isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-phenyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-methylcyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-quinolyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2,5-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isopropylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(3-thienylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,6-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[[(1R)-1-cyclonexylethyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-[3-(hydroxymethyl)phenyl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-difluoro-5-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-hydroxy-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-fluoro-4-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(6-methylcyclonex-3-en-1-yl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(diethylamino)-4-methyl-2-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(1H-indol-5-yloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-thienylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[methyl-[2-(3-pyridyl)ethyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-difluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(1-naphthyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4-dimethoxypyrimidin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-5-iodo-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isobutoxy-6-methyl-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[[3-(dimethylamino)phenyl]methoxyl-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(1,3-benzodioxol-5-yloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(2-fluorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-5-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-cyclohexylpropoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[(1R)-1,2-dimethylpropoxy]-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(dimethylamino)pyrimidin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-cyclopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(4-phenylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(3,3-dimethylbutoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(cyclopentylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideisopropyl4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-2-tert-butyl-6-[(4S)-22,4-trimethylpyrrolidin-1-yl]-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate6-(4-chlorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-methyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-methoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(tetrahydropyran-4-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-6-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4,5-trifluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutylpyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2,4-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3,3-dimethylcyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3,4,-dimethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxy-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[cyclopropylmethyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(5-fluoro-2-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-5,5-dimethyl-cyclohexyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[1-(1-naphthypethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-ethoxy-5-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluoro-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN[[6-(cyclopentylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1H-indol-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[2-(trifluoromethyl)pyrrolidin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-[(3S)-tetrahydrofuran-3-yl]oxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(1-methylcycloheptoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-2,4-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[[6-(1,7,7-trimethylnorbornan-2-yl)oxy-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideethyl3-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]benzoateN-[[6-(3,4-dichlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-2-cyclohexylvinyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(3-chlorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(hydroxymethyl)-5-methoxy-phenyl1-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-chlorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(5-fluoro-2-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-pyridylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclopentyl-1,2-dihydroxyethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxy-5-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[2-(4-methoxyphenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2,3-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(5-quinolylamino)-2-pyridylsulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-isopentyloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-cyanophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(3S)-1-benzylpyrrolidin-3-yl]oxy-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[2-(2-isopropoxyethoxy)-6-methyl-4-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-methoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(4-methyl-2-pyridyl)amino]-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-tert-butylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluoro-4-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(5-methyl-2-propoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-methoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[4-(1-piperidyl)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(hydroxymethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isobutoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2-methoxyphenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,6-dimethoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3,5-dimethylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-phenylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-methyl-4-propoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-cyanophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-norbornan-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridyl]sulfonyl}-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2,4-difluorophenyl)methoxyl-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(cyclopentoxy)-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(6-methoxy-2-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(4-fluoroanilino)-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxy-6-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2,2-difluoro-1,3-benzodioxol-5-0)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,5-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(2,4,6-trifluoroanilino)-2-pyridyl]sulfonyl}-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-benzyl-1-piperidyl)-2-pyridyl]sulfonyl}-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(3-isopropylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(1S,2S)-2-methylcyclopentoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(1-phenylpyrazol-4-yl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1-isobutylpyrazol-3-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(2,3-dihydro-1,4-benzodioxin-3-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-methylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(4-pyrazol-1-ylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(4-phenylbutylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideethyl4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]benzoateN-[[6-(3-benzylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluoro-3-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1H-indol-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methyl-1-naphthyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butyl4-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylateN-[[6-(1,1-dimethylbutoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-([6-(tetrahydrofuran-2-ylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(p-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideethyl3-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(2,2,4-trimethylpyrrolidin-1-yl)-3-pyridyl]-4-methoxy-benzoateN-[[6-(3-methoxypropylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(1-naphthylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-methyl-2-pyrrol-1-yl-propoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(5-ethoxy-2-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-((6-aminopyridin-2-yl)sulfonyl)-6-(tert-butyl)-2-(2,2-dimethyl-3-(tetrahydro-2H-pyran-4-yl)pyrrolidin-1-yl)nicotinamidemethyl6-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]pyridine-3-carboxylateN-[(6-(3-tert-butylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[3-(trifluoromethoxy)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[3-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(4-chlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(2-thienyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-cyclohex-2-en-1-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-hydroxy-4-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(5-ethoxy-2-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-isobutyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-naphthylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(3-methoxy-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(4-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3,4-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(1H-indazol-4-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-3-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2,4-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(4,6-dimethyl-2-pyridyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(3-thienyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2,3-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-dihydrobenzofuran-7-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-chloro-2-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3,3-difluoropyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-butoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(3-methoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(1,3-benzodioxol-5-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(6-isopropoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-isopropylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-isopropylcyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-hydroxy-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[4-(4-pyridylmethyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(o-tolyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(3-chloro-5-cyano-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2,5-dimethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-tert-butylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-thienylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-chlorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(m-tolyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-cyanophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl}-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(1S)-1-phenylethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(4-isopropylphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(cyclobutylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(5-fluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-2-pyridyl]sulfonyl}-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(3-hydroxy-2-methyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(1-methylindol-5-yl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,5-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(1-methylbutylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(2-methyl-1,3-benzothiazol-5-yl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(isopropylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(cyclooctylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butyl(2S)-1-[3-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyridyl]pyrrolidine-2-carboxylateN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-phenoxyethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(4-ethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-phenylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(2-chloro-5-isopropoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-decalin-2-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-[1-(4-pyridyl)ethoxy]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethyl-2,4-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[[6-(4-ethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-dimethylisoxazol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butyl(2R)-1-[3-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pyridyl]pyrrolidine-2-carboxylateN-[[6-(2,4-dichloroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2-methylcyclohexyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[1-(methoxymethyl)propylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-fluoro-3-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(trifluoromethoxy)phenyl]-2-[(4S)-22,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[4-(1-methylbutyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-ethoxy-2,5-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-isopropoxy-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1-isobutylpyrazol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl}-6-(3-hydroxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(2,3-dimethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[4-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-ethoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxy-5-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-methoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-[3-(cyclopropylmethyl)-2,2-dimethyl-pyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(2-phenylacetyl)amino]-2-pyridyl]sulfonyl]-6-[1-(2-phenylacetyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-[3-(hydroxymethyl)-5-methoxy-phenyl]-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-4-methyl-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(1,3-benzodioxol-4-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(cyclohexylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidetert-butyl2-[methyl-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]acetateN-[(6-(cycloheptoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideethyl4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]piperidine-1-carboxylateN-[(6-(4-pyrazin-2-ylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-indolin-1-yl-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-ethoxy-4-methyl-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-N-methyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3,5-difluorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[[2-(trifluoromethyl)phenyl]methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(4-chlorophenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(3-chlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamide6-(3-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methoxy-2-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(6-methyl-8-azaspiro[3.4]octaN-8-yl)pyridine-3-carboxamideN-[[6-(1-naphthylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-(trifluoromethyl)pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(2-chlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(5-isoquinolyiamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(3-benzyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide6-(3-ethoxy-5-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isobutyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-naphthyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-[(3R)-tetrahydrofuran-3-yl]oxy-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(3,5-difluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(2-isopropoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3,4-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[4-(6-methyl-2-pyridyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(4-tert-butylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2,3-dimethylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-dimethylaminophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1-isopropylpyrazol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[4-(trifluoromethyl)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3,5-dimethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(6-methyl-2-pyridyl)methoxy]-2-pyridyl]sulfonyl]-2-(2.2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(5-fluoro-2-hydroxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-benzyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-chlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(3-cyanophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-hydroxy-3-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-difluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(1-isobutylpyrazol-3-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-cyanophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-ethylbutylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-isopropoxy-6-methyl-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[butyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-furylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2,6-dimethoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2-methoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-3-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(2-chlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[3-(cyclopentoxy)-5-methyl-phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-aminophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-cyano-4-fluoro-anilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-cyclopent-3-en-1-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[[(1R)-1,2-dimethylpropyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(dimethylamino)-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-methylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide(3S)-2-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamayl]-2-pyridyl]-3,4-dihydro-1H-isoquinoline-3-carboxylicacidN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-tert-butyl-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-methylmorpholin-4-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[2-(2-ethoxyethoxy)ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-acetylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-tetrahydropyran-4-ylethoxy)-2-pyridylsulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-methyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-fluorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(8-quinolyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4,5-difluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butylN-[4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]carbamateN-[[6-(4-methylcyclohexoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(trifluoromethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(1H-indol-4-yloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3,3a,4,5,6,6a-hexanydro-1H-cyclopenta[c]pyrrol-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3,4-difluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(cyclopropylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-methoxyethyl(propyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[1-(3,3-dimethylbutanoyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[isopentyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluoro-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2,2-difluoroethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-tetrahydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1-methylindol-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-isopropoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-ethoxyethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-fluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(3,5-dimethoxyanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[6-methyl-8-azaspiro[3.4]octan-8-yl]pyridine-3-carboxamideN-[[6-[2-(2-pyridyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-isopropoxypyrazol-1-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-methylcyclohexen-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isobutylamino)-5-methyl-2-pyridyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxy-6-methyl-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[[6-(trifluoromethyl)-2-pyridyl]methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-chlorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl]sulfonyl]-6-(4-isopropylphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-methoxy-3-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(1,2-dihydroxy-3,3-dimethylbutyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(cyclobutoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(1-cyclopropylethoxy)-5-fluoro-2-(2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-fluoro-5-isobutoxy-phenyl)-N-(3-pyridylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(3-chlorophenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-methoxy-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[3-(trifluoromethyl)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3,4-dihydro-2H-quinolin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[4-(2-dimethylaminoethyl)-1-piperidyl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(6-ethoxy-3-pyridyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(5-chloroindolin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-2-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-acetamidoanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,5-difluoro-4-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(1H-indazol-5-ylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2,6-dichlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(m-tolylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(3S)-3-fluoropyrrolidin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(5-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-isobutylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(tetrahydrofuran-3-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(trifluoromethyl)anilino]-2-pyridyl]sulfonyl}-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-chlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidetert-butylN-methyl-N-[2-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]ethyl]carbamateN-[(2-amino-3-pyridyl)sulfonyl]-6-(1-methylindol-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(3,4-dichlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-ethoxy-3-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-ethoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl}pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(1-benzylpyrrolidin-3-yl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[1-(2-fluorophenyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(3-fluorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-ethoxy-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2,2-dimethylpropoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(4-isopropylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[1-(2-phenylacetyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4.-isoquinolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(6-methoxy-2-pyridyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4.-trimethylpyrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(3,5-difluorophenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-fluoro-6-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-hexylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(m-tolyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethyl-3-tetrahydropyran-4-yl-pyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-tert-butyl-N-[(6-[(4-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-chlorophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-methoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-methoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(trifluoromethyl)cyclohexyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(3-acetamidophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(1-methylcyclopropyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-cyanophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-(p-tolyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butylN-[4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]cyclohexyl]carbamate6-(3-methoxy-4-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-imidazol-1-ylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidemethyl1-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]piperidine-4-carboxylateN-[[6-[3-(dimethylamino)phenoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(5-fluoro-6-methoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-phenyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-2-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-isobutoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-quinolylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxy-2,3-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[2-(4-piperidyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-fluoro-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-methoxy-3-pyridyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-fluoro-3-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,5-difluoro-4-methoxy-phenyl)-2-[(4S)-2,24-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[(2S)-2-methylbutoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-ethoxy-4-fluoro-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4-methylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-chlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(3,5-difluorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(4-tert-butylphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-morpholino-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(3-methoxyphenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[[6-(trifluoromethyl)-3-pyridyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-isobutyl-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-hydroxy-2-naphthyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-methoxy-2-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(1R)-1-methyl-2-phenyl-ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-fluoro-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-5-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclohexyl-1,2-dihydroxyethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[[6-(trifluoromethyl)-3-pyridyl]methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1H-indol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-hydroxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluoro-2-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-isopropylphenyl)-N-[(2-exo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-cyanoanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-methoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-isopropylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-y)pyridine-3-carboxamideethyl1-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]piperidine-4-carboxylate6-(3-fluoro-2-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidemethyl3-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]benzoateN-[(2-amino-3-pyridyl)sulfonyl]-5-(4-methoxy-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidetert-butyl3-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propanoate6-(3,5-difluoro-2-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxmideN-[(2-amino-3-pyridyl)sulfonyl]-6-[6-(2-ethoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3-isopropylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-methoxy-5-ethyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl)-6-[6-(2,2-dimethylpropylamino)-2-pyridyl]-2-[(4S)-2,2,4-trimethypyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[2-(p-tolyl)ethylamino]-2-pyridyl)sulfanyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(5-chloro-2-methoxy-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[4-(2-pyridylmethyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-fluoro-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamidemethyl4-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]piperazine-1-carboxylateN-[(6-(3-furylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-phenoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(trifluoromethyl)cyclohexen-1-yl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-ethoxy-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1yl]pyridine-3-carboxamideN-[[6-(2,6-difluoroanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-6-[2-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[3-(dimethylamino)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[1-(cyclohexylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(1-cyano-1-methyl-ethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(1-oxotetralin-6-yl)oxy-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(4-fluorophenyl)methoxy]-2-pyridyl]sulfonyl}-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-ethoxyanitino)-2-pyridyl]sulfonyl}-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-fluoro-5-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-propoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-butoxypropylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(2-methoxy-5-methyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[4-(diethylamino)anilino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(3,4-difluorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(methylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidetert-butyl(2R)-1-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]pyrrolidine-2-carboxylatetert-butylN-[(3R)-1-[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]pyrrolidin-3-yl]carbamateN-[(6-amino-2-pyridyl)sulfonyl]-2-(4-tert-butyl-2,2-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(trifluoromethoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-chloro-3-propoxy-phenyl)-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-N-[[6-(pent-4-ynoylamino)-2-pyridyl]sulfonyl]pyridine-3-carboxamide6-(2-isopropoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-fluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(difluoromethoxy)-3-methyl-phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-chloro-5-methoxy-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-oxazol-5-ylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3-isopropoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[3-(3-methylpyrazol-1-yl)propylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-methoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-cyclopropylethy)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-hydroxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(4-hydroxy-3,5-dimethyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(2-ethoxyphenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(3-isobutoxy-5-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3,4-difluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-pyrrolidin-1-yl-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-3-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(4-pyrrol-1-ylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-methoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[4-(1-ethylpropyl)piperazin-1-yl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluorophenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2,3-difluoro-4-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(tert-butylcarbamoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(3-acetylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-chloro-4-methoxy-anilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(3-methylanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethyl-4-(trifluoromethyl)pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[[6-(cyclopropylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(4-methoxy-2,6-dimethyl-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[5-methyl-6-[(1R)-1-methylpropoxy]-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(3-cyclopropyl-2,2-dimethyl-pyrrolidin-1-yl)pyridine-3-carboxamide6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[(2-oxo-1H-pyridin-3-yl]sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-[(4-methoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(5-fluoroisoindolin-2-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-methoxyethoxy)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2,3-dihydrobenzofuran-7-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(2-cyanophenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(4-chlorophenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2.4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2,2-dimethylmorpholin-4-yl)-5-fluoro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-(5-benzyloxy-2-methyl-phenyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(6,6-dimethyl-7-azaspiro[3.4]octan-7-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(hydroxymethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-(2-chloro-5-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-hydroxy-3-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(trifluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[6-methyl-8-azaspiro[3.4]octan-8-yl]pyridine-3-carboxamideN-[[6-(chroman-3-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-[1-(2-cyclohexylacetyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-furylmethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(5-chloro-2-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(3-pyrrol-1-ylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-cyclohexylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(2-propoxyethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[4-(2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-isobutoxypyrazol-1-yl)-2-(6-methyl-8-azaspiro[3.4]octan-8-yl)pyridine-3-carboxamide6-(2-fluoro-5-methoxy-phenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxy-2,6-dimethyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3,5-difluoro-4-isopropoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-methylpyrrolidin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(4-ethynylphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-naphthyloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(2,2-dimethylbutanoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-fluoro-4-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-hydroxy-3-methoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-ethoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[[4-(trifluoromethyl)phenyl]methoxyl-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-benzyloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-butyl-1,4-diazepan-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-pyrimidin-2-ylpiperazin-1-yl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideisopropyl5-[5-[(6-amino-2-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylateN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-isopropoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideisopropylN-[6-[[6-(1,2,3,6-tetrahydropyridin-5-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]carbamateN-[[6-[2-(2-fluorophenyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-(3,5-dimethylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(4H-1,3-benzodioxin-2-ylmethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(5-fluoro-6-methoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(2-isobutoxyphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-cyclopentylethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-(4,4-difluoro-2,2-dimethyl-pyrrolidin-1-yl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamideN-[[6-[2-(2-chlorophenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(2-cyclohexylacetyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-3-fluoro-4-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]benzamide6-(2-isopropylphenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(1H-indol-4-yl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-methoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-anilino-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2,3-difluorophenyl)methylamino]-2-pyridyl[sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[4-(trifluoromethyl)-1-piperidyl]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(4-ethoxyphenyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2-methyl-8-quinolyl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[4-(difluoromethyl)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(5-chloro-2-methoxy-phenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-methoxy-4-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[(E)-5-methylhex-1-enyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(3-methylbut-2-enoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-5-[4-(trifluoromethoxy)phenyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[1-(3,3-dimethylbutanoyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(6-ethoxy-5-methyl-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3,5-difluorophenyl)-N-[(2-oxo-1H-pyridin-3-yl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-fluoro-2-hydroxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2,4,6-trifluorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(5-chloro-2-pyridyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidetert-butyl2-[5-[(2-amino-3-pyridyl)sulfonylcarbamoyl]-6-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]-2-pyridyliindole-1-carboxylateN-[(6-amino-2-pyridyl)sulfonyl]-6-(4-isopropoxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-(2-cyanoanilino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(5-fluoro-2-methyl-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-5-(2-cyclopentyl-1,2-dihydroxyethyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[[6-[(3,4-dimethoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3,5-dichlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3,4-dimethoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(3-ethoxy-4-fluoro-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(4-methoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(1,3,5-trimethylpyrazol-4-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[[2-(1-piperidyl)-3-pyridylsulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-tetranydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-tetranydropyran-2-yl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(2-ethoxyethoxy)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-4-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-(2-ethoxyethoxy)ethyl-methyl-amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[2-ethoxyethyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(2-ethoxyethylamino)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[isopropyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-(isopropylamino)-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[6-[ethyl(methyl)amino]-5-methyl-3-pyridyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-((2-aminopyridin-3-yl)sulfonyl)-6′-(((S)-1-hydroxypropan-2-yl)oxy)-6-((S)-2,2,4-trimethylpyrrolidin-1-yl)-[2,3′-bipyridine]-5-carboxamideN-[(2-amino-6-methoxy-3-pyridyl)sulfonyl]-6-(6-isopropoxy-3-pyridyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(cyclobutylmethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(cyclopropylmethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(2,2-dimethylpropoxy)-4-methyl-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(cyclopropyl)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(phenyl)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-[3,3,3-trideuterio-2,2-bis(trideuteriomethyl)propoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(S)—N-((2-aminopyridin-3-yl)sulfonyl)-6-methoxy-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamideN-[(2-amino-3-pyridyl)sulfonyl]-6-(2-ethoxyethoxy)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[2-(2-ethoxyethoxy)ethoxy]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide6-(3,5-dimethylphenyl)-N-[(6-isopentyloxy-2-pyridyl)sulfonyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-[3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]phenyl]-2-{(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-6-(3-bicyclo[2.2.1]hept-2-enyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(1-methylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(2-amino-3-pyridyl)sulfonyl]-6-[3-(1-methylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamideN-[(6-amino-2-pyridyl)sulfonyl]-2-[(2R,5S)-2,5-dimethylpyrrolidin-1-yl]-6-[6-[1,2,2,2-tetradeuterio-1-(trideuteriomethypethoxy]-3-pyridyl]pyridine-3-carboxamide6-(tert-butyl)-N-((6-((4-methoxybenzyl)amino)pyridin-2-yl)sulfonyl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide6-tert-butyl-N-[(6-[(4-methoxyphenyl)methoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(1,3-benzodioxol-5-ylmethoxy)-2-pyridyl]sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[(E)-but-2-enoxy]-2-pyridyl]sulfonyl]-6-tert-butyl-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide6-tert-butyl-N-[(6-isopentyloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-chloro-5-fluoro-phenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-(2,3-dichlorophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-phenethyloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(2,5-dimethoxyphenyl)methylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[cyclopropylmethyl(propyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-[isopropyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[cyclopropylmethyl(propyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[isopropyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(3-cyanophenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(diethylamino)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2,1,3-benzoxadiazol-5-yloxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidemethyl4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]oxy]benzoateN-[[6-[(2-methyl-1,3-benzothiazol-5-yl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-acetylphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(6-methyl-2-pyridyl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-methoxy-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(1-oxoindan-5-yl)oxy-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[3-methoxypropyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(4-pyridyl)ethylamino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[(5-chloro-2-pyridyl)oxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-chroman-4-yloxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(1-piperidyl)phenoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(4-tert-butoxyphenoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[2-(3-fluorophenyl)ethoxy]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[(6-but-2-ynoxy-2-pyridyl)sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-(2-aminoethoxy)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamidetert-butylN-[4-[[6-[[2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]phenyl]carbamateN-[[6-[(2-chlorophenyl)methyl-methyl-amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamideN-[[6-[[(1R)-1,2,2-trimethylpropyl]amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide.N-[[6-[isobutyl(methyl)amino]-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide;orN-[[6-(2-methyl-1-piperidyl)-2-pyridyl]sulfonyl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide.214. A compound or pharmaceutically acceptable salt thereof, wherein thecompound has the following formula:


215. A pharmaceutical composition comprising: (i) the compound orpharmaceutically acceptable salt thereof according to claim 214; and(ii) a pharmaceutically acceptable carrier.
 216. The pharmaceuticalcomposition of claim 215, further comprising an additional therapeuticagent having the following structural formula:

or a pharmaceutically acceptable salt thereof.
 217. The pharmaceuticalcomposition of claim 215, further co p sing an additional therapeuticagent having the following structural formula:

or a pharmaceutically acceptable salt thereof.
 218. The pharmaceuticalcomposition of claim 215, further co p sing additional therapeuticagents having the following structural formulae:

or pharmaceutically acceptable salts thereof.
 219. A compound orpharmaceutically acceptable salt thereof, wherein the compound has thefollowing formula:


220. A pharmaceutical composition comprising: (i) the compoundpharmaceutically acceptable salt thereof according to claim 219; and(ii) a pharmaceutically acceptable carrier.
 221. The pharmaceuticalcomposition of claim 220, further comprising an additional therapeuticagent having the following structural formula:

or a pharmaceutically acceptable salt thereof,
 222. The pharmaceuticalcomposition of claim 220, further comprising an additional therapeuticagent having the following structural formula:

or a pharmaceutically acceptable salt thereof.
 223. The pharmaceuticalcomposition of claim 220, further comprising additional therapeuticagents having the following structural formulae:

or pharmaceutically acceptable salts thereof.
 224. A compound orpharmaceutically acceptable salt thereof, wherein the compound has thefollowing formula:


225. A pharmaceutical composition comprising: (i) the compound orpharmaceutically acceptable salt thereof according to claim 224; and(ii) a pharmaceutically acceptable carrier.
 226. The pharmaceuticalcomposition of claim 225, further comprising an additional therapeuticagent having the following structural formula:

or a pharmaceutically acceptable salt thereof.
 227. The pharmaceuticalcomposition of claim 225, further comprising an additional therapeuticagent having the following structural formula:

or a pharmaceutically acceptable salt thereof,
 228. The pharmaceuticalcomposition of claim 225, further comprising additional therapeuticagents having the following structural formulae:

or pharmaceutically acceptable salts thereof,
 229. A compound orpharmaceutically acceptable salt thereof, wherein the compound has thefollowing formula:


230. A pharmaceutical composition comprising: (i) the compound orpharmaceutically acceptable salt thereof according to claim 229; and(ii) a pharmaceutically acceptable carrier.
 231. The pharmaceuticalcomposition of claim 230, further comprising an additional therapeuticagent having the following structural formula:

or a pharmaceutically acceptable salt thereof,
 232. The pharmaceuticalcomposition of claim 230, further comprising an additional therapeuticagent having the following structural formula:

or a pharmaceutically acceptable salt thereof.
 233. The pharmaceuticalcomposition of claim 230, further comprising additional therapeuticagents having the following structural formulae:

or pharmaceutically acceptable salts thereof.